骨組織におけるヒアルロン酸の用途は何ですか?

外傷、腫瘍、先天性奇形、感染症などの病理的要因による骨組織の欠陥は、臨床整形の問題の一つであり、この問題を解決するための主要な方法は骨移植である[1]。骨移植は、主に自家の骨移植、同種の骨移植または同種の骨移植に分けられるが、自家の骨移植は自家の骨量が不足し、感染しやすく、患者に再外傷を与えるなど問題が多い。同種の骨移植は高価である。同種骨移植は高価であり、免疫拒絶反応を起こす。骨修復材料の代替として組織工学的に作製された生体材料骨は、生体修復材料の欠陥を回避することができます[2]。

Ideal 組織scaffolds should have some properties: good biocompatibility; appropriate biodegradability とeventual disappearance; good cell-セルinterface ののmaterial にallow cell adhesion, promote cell growth, とretaでcell differentiation; three-dimensional porous structure とgood porosity to allow cell infiltratiにとvascularisation; とのcertaでdegree のmechanical strength, which is easy to fabricate [3]. Hyaluronic 酸is のnew hot spot でのresearch の骨biomaterials. Hyaluronic 酸hとしてのhigh degree のviscoelasticity, plasticity, excellent water absorption, permeability とgood bioabsorbability, and is non-immuno-antigenic. Modified ヒアルロン酸 not only maintains のoriginal superior properties, but also 改善its properties and makes it more adaptable to the 人間environment [4]. Therefore, ヒアルロン酸is now the hot spot のbioengineering 骨組織materials.

変形性関節症治療におけるヒアルロン酸の1アプリケーション

Osteoarthritis is one のthe most commにknee injuries and joint diseases, and injection のヒアルロン酸(sodium vitrate) hとしてbecome のcommon treatment ためosteoarthritis. According to the literature, Manicourt etal[5] reported that the content of ヒアルロン酸increased when the physiological stress でthe joint increased, which suggests that ヒアルロンacid, としてan important component of proteoglycan polymers, may have のbuffering effect on stress. Hyaluronic 酸in synovial fluid has の大型amount of negative charge when combined とproteins, and it has strong water absorption and high viscosity. Proteoglycan polymers increase the lubricity and viscoelasticity of the synovial fluid and provide a high affinity between the lubricant and the articular cartilage. Hyaluronic acid and proteoglycans adhere tightly to the joint surfaces and act as lubricants, thus reducing the resistance to joint 運動 and protecting the articular 軟骨からexcessive mechanical wear.

Kawasaki et al.[6] reported that ヒアルロンacid increased the 合成of chondroitin sulphate によってchondrocytes 培養in collagen gels, and Stove et al.[7] found that hyaluronic acid decreased the production of proteoglycans by chondrocytes in osteoarthritic patients, but hyaluronic acid inhibited the reduction of proteoglycans induced by IL-1, and Kikuchi et al.[8] reported that exogenous hyaluronic acid increased the production of chondroitin in seaweed beads. Kikuchi et al.[8] reported that exogenous hyaluronic acid caused the movement of newly synthesised proteoglycans from pericellular to distal 行列of chondrocytes in algal bead medium and 軟骨tissues, suggesting that hyaluronic acid may have an effect on the 分布and movement of proteoglycans, and may have a protective effect on the cartilaginous extracellular matrix. In addition, hyaluronic acid is a scavenger of free radical cellular debris, embedding itself in the polymer meshwork formed by hyaluronic acid and metabolising it rapidly within the joint, thus contributing to the elimination of cellular debris and assisting in the elimination of cartilage cellular metabolites.

2軟骨や骨の欠陥の修復におけるヒアルロン酸と生体因子の組み合わせ

2.1軟骨細胞の増殖を促進する

軟骨が損傷した後、自身の修復能力に限界があり、軟骨細胞を移植する方法が注目されている。研究では、インスリン様成長因子1が軟骨修復に重要な役割を果たしていることが示されている。ヒアルロン酸は軟骨基質の主要成分の一つです。論文によると、インスリン様成長因子-1は、関節軟骨細胞に調節効果を持つことが確認されている最初の成長因子である。しかし、半減期が短く、分解しやすく、内部要因による干渉を受けやすいため、その影響は限定的である[9-10]。

Hyaluronic acid is negatively charged, has strong hydrophilicity and high adhesion, and has strong affinity とchondrocytes. In addition, hyaluronic acid has the function of chondroinduction, which can provide nutrition ためarticular chondrocytes, participate in the synthesis of proteoglycan polymers, act as a building block on the surface of chondrocytes through glycoproteoglycans, and promote the 拡散of superficial joints, maintain the thickness of uncalcified cartilage, and promote the repair of articular cartilage とdegenerative changes to a certain extent [11-12]. It has been reported in the literature that the combination of hyaluronic acid and insulin-like 成長factor-1in the in vitro culture of 人間articular chondrocytes can help to maintain the stability of the phenoタイプof hyaluronic acid chondrocytes and promote the proliferation of the cells, thus providing a new method to obtain high-density autologous chondrocytes in vitro that have normal functions, and also providing 実験bases ためthe study of autologous chondrocyte transplantation or cartilage 組織engineering [13].

異2.2合成移植片移植

The commonly used material ためthe repair of 部分骨欠陥is allogeneic freeze-dried bone, but due to the weak induced activity of allogeneic freeze-dried 骨and its poor osteogenicability, it only serves as a 骨組みためosteoconduction in the process of repair. The development of modern 分子biology technology has led to a deeper understanding of the osteogenic and osteoinductive activities of 骨成長factors, and 骨grafts を含む骨成長factors combined とsuitable carriers have become a new trend in the treatment of bone defects. It has been reported in the literature that implantation of 基本線維芽細胞成長要因fused とhyaluronic acid gel and composite freeze-dried bone into the bone defect area has a good effect on repairing bone defects [14-15]. BFGF can stimulate the proliferation of mesenchymal cells, chondrocytes and osteoblasts, and induce the differentiation of mesenchymal 細胞to bone and chondrocytes; stimulate the proliferation of vascular endothelial cells, and promote the formation of neovascularisation [16].

Based on the above biological properties of basic 線維芽細胞growth factor, it was compounded とhyaluronic acid and freeze-dried bone to promote the growth of osteoblasts by taking advantage of their respective strengths. The histological sections of this experiment showed that: in the early stage, a large number of mesenchymal 細胞could be seen in the bone defect area of the complex を含むbasic fibroblasts, hyaluronic acid and lyophilized bone, bridging the bone fracture in the form of cords, and showing a tendency of differentiation to osteoblasts and chondroblasts, とthe appearance of new bone and cartilage islands; in the mid-stage, the neovascularisation grew into the area, and the cartilage tissues matured in the process of ossification, とthe islands fused together into a piece to form a braided bone. The amount of new bone and cartilage in the hyaluronic acid and lyophilised bone group was significantly lower than that in the basic fibroblast, hyaluronic acid and lyophilised bone complex group, and the distribution was uneven [17].

报道が出て、文学の役割の基礎線維芽細胞成長因子になることは、あの間充織の拡散を刺激細胞骨修復の初めですが—も後者軟骨クズ成長因子などもosteoinductiveな要因として働き骨や自分の軟骨細胞に分化する骨刺激開始過程の修繕欠陥ですんだ。新卵巣形成の成長に伴い、移植片への血液供給が再確立され、内軟骨骨化が促進され、移植片の置換と新しい骨の成熟が促進され、治癒時間が短縮される。マトリクスとしてのヒアルロン酸は、細胞成長のための栄養素と三次元空間を提供し、骨組織の修復を促します[18]。

3改変ヒアルロン酸複合体の生体骨組織への応用

Hyaluronic acid is easily degraded and its degradation time is closely related to its 分子weight. Therefore, in order to prolong the degradation time of hyaluronic acid molecules in the organism, it is necessary to prepare a derivative with a much higher molecular 体重than that of natural sodium hyaluronate molecules, i.e., cross-リンクsodium hyaluronate derivatives, through chemical modification. The principle of preparation of cross-linked sodium hyaluronate is to use one or more combinations of chemical cross-linking agents, using the cross-linking agent (oxidation, reduction, esterification, aldolisation, etc.) to make the hyaluronic acid molecules undergo a chemical reaction, so that the hyaluronic acid molecules or hyaluronic acid and the cross-linking agent cross-linking together [19].

The cross-linking reaction lengthens the hyaluronic acid molecules, increases or decreases their solubility properties, and improves their mechanical strength or resistance to degradation by the body. Therefore, various chemical modifications of hyaluronic acid have been carried out and applied to the study of bone 組織engineering. Martinez-Sanz et al. used aminopropanetriol as a cross-linking agent to form perylene-HA matrix by amidation, and this hyaluronic acid derivative complexed with bone-forming protein2was proved to be non-cytotoxic and histocompatible in in vitro tests. When the 化合物was injected into the cranial surface of rats, histological examination showed that there was new bone formation on the cranial surface after 8 weeks, and the expression of osteocalcin and bone 骨髄angiogenesis was also high, which means that perylenic-hyaluronic acid can act as a carrier of osteoblast2and can promote bone expansion. This finding has been confirmed by subsequent studies [18-19].

Bae et al.[20] observed the effects of photocured hyaluronic acid in combination with 何ですかon bone regeneration. The results showed that the viscoelasticity of the 2-aminoethyl methacrylate-hyaluronic acid matrix was significantly improved compared with that of hyaluronic acid, and that it could regulate the stable and slow release of simvastatin, which promoted the increase of MC3T3-E1 cell proliferation. MC3T3-E1 cells proliferated and differentiated, thus inducing new bone formation, i.e., photo-hyaluronic acid combined with 何ですかcould be a good scaffold ためtissue-engineered bone.

Lisignoli et al.[21] investigated the osteogenesis of hyaluronic acid derived from its esterification, benzyl ester of hyaluronic acid, in combination with bone marrow 腸管基底cells in a murine model of large bone defects, where the cells were treated with alkaline fibroblast growth 要因supplemented or not with supplemented mineralisation medium, and the results showed a significant increase in the viscosity of the matrix. Cells were cultured in mineralisation medium with or without alkaline fibroblast growth 要因supplementation, and defect healing was evaluated after 40, 60, 80 and 200 d. In vivo studies have demonstrated that benzyl hyaluronate is a suitable vehicle ためbone defect repair and significantly accelerates bone mineralisation when combined with bone marrow stromal cells and alkaline fibroblast growth factor.4 Hyaluronic acid complexes with growth factors are also suitable ためbone repair.

4ヒアルロン酸複合体と骨組織の成長因子

Hyaluronic acid is a good carrier of growth factors in bone repair, but its main drawback as a scaffold is its low cell 癒着properties, whereas integrins are a major family of cell surface receptors that mediate the adhesion of cells to the extracellular matrix.23 Kisie et al. [24] covalently bonded hyaluronic acid with specific リガンドon integrins to form a hyaluronic acid-integrin matrix and investigated the effects of hyaluronic acid-integrin complexes in large bone defects in a murine model.

Compared with the control group, the hyaluronic acid-integrin ハイドロshowed a significant increase in cell adhesion and bone growth 要因delivery, which further 拡張the osteogenic 潜在of recombinant human osteoblast-2. Therefore, the hyaluronic acid-integrin matrix can be used as a growth factor 配達vehicle, and has a potential value for clinical application. The study of hyaluronic acid complex is the hot spot of biomaterials research nowadays, this kind of complex combines the advantages of its own material and makes up for its own shortcomings, which has the incomparable advantages of other materials, but there is no in-depth study on the histocompatibility, inflammation and degradability of this kind of composite, which may be the hot spot of future research.

5つの問題と展望

Hyaluronic acid is a biodegradable biomaterial with good biocompatibility, and its hydrophilicity plays an important role in cell adsorption, growth and differentiation. It can be used as a temporary skeleton to support and stimulate the growth of new bone tissues, and then it will be gradually degraded to be replaced by new bone tissues after completing the mechanical support function for a certain period of time. A large number of experimental studies have proved that hydrogelsbased on hyaluronic acid and compounded with insulin-like factor, growth factor and BMP-2can provide a growth environment for chondrocytes, osteoblasts and myeloid cells, and their three-dimensional structure, good water solubility, no immune reaction and good degradability are the advantages of hyaluronic acid [28-29], but there are still a lot of difficulties that need to be overcome if they are applied in clinical practice. Hyaluronic acid has been discovered for more than 80 years. Hyaluronic acid has been discovered for more than 80 years, and has been used in ophthalmology, joint surgery and other research fields [30-33], and it is a new development to use it as the basis of biomaterials for biological tissues. In recent years, there have been many experimental researches on biomaterials using hyaluronic acid as scaffolds, and it is hoped that it can be really used in the clinic in the near future.

参照

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