Evaluation of the effect of incorporation of dibutyryl cyclic adenosine monophosphate in an in situ-forming hydrogel wound dressing based on oxidized alginate and gelatin

Cyclic adenosine monophosphate (cAMP) has long been regarded as a second messenger and a regulator of human keratinocyte proliferation. To explore more effective wound management, dibutyryl cyclic adenosine monophosphate (DBcAMP), a lipophilic analog of cAMP was incorporated into an in situ-forming hydrogel wound dressing based on periodate-oxidized alginate and gelatin. In vitro release of DBcAMP from the matrix into phosphate buffered saline was slow and increased with time. Only 50-60% of the compound was released into the medium over a period of 2 days suggestive of a sustained release into the wound bed over a period of few days. The wound-healing efficacy of the DBcAMP-incorporated dressing was evaluated on experimental full-thickness wounds in a rat model. It was found that dressing promoted wound healing leading to complete re-epithelialization of wounds within 10 days, whereas control wounds took 15 days for complete re-epithelialization. Data obtained in this study showed that the presence of DBcAMP accelerated healing and re-epithelialization of full-thickness wounds.     

藻酸盐银联合水凝胶敷料对慢性创面愈合的作用

背景：研究发现藻酸盐及水凝胶敷料等均可促进创面愈合,而新型敷料藻酸盐银联合水凝胶敷料,对于难治慢性创面的愈合作用尚不清楚。 目的：观察藻酸盐银联合水凝胶敷料对慢性创面治疗的作用。 方法：选择江苏省人民医院烧伤整形科住院慢性创面患者34例,随机分为2组：治疗组应用藻酸盐银联合水凝胶敷料序贯换药;对照组采用1%磺胺嘧啶银冷霜抹在凡士林纱布上外敷,于治疗后7,10,14,17,21 d进行创面分泌物细菌培养、观察创面愈合情况及速度、药物不良反应、换药时创面痛感、肉芽破坏等情况。 结果与结论：治疗组创面细菌检出率明显低于对照组(P < 0.05)。治疗组创面愈合时间比对照组平均缩短约6 d,创面愈合速度较对照组明显加快(P < 0.05)。两组均无药物不良反应,治疗组创面换药时无明显疼痛感,肉芽组织无明显破坏。提示藻酸盐银联合水凝胶敷料序贯治疗慢性创面具有显著抗菌及促进创面肉芽组织和上皮再生、促进创面愈合的作用,且无不良反应。     

组织工程生物绷带及敷料在创伤修复领域中的应用

背景：医用敷料作为伤口处的覆盖物,在伤口愈合过程中,可以替代受损的皮肤起到暂时性屏障作用,避免或控制伤口感染,提供有利于创面愈合的环境。如何既能快速固定、有效止血,又可以减轻或避免止血后对伤肢血循环造成的不利影响,加快伤口愈合、减轻伤痛是创伤急救医学亟待解决的难题。 目的：文章综述了医用生物敷料在创伤修复领域中的应用现状及研究进展,揭示其发展前景,为其在创伤修复过程中的应用提供理论基础。 方法：应用计算机检索CNKI和PubMed数据库中1998-01/2008-12关于医用生物敷料的文章,在标题和摘要中以“医用敷料;生物材料,壳聚糖,水凝胶,组织工程”或“medical dressing,chitosan”为检索词进行检索。选择文章内容与创伤修复相关,同一领域文献则选择近期发表或发表在权威杂志文章。初检得到146篇文献,中文107篇,英文39篇,根据纳入标准选择38篇文章进行综述。 结果与结论：就目前临床使用及研究的医用敷料,根据其所用的材料将其分成了天然材料和合成高分子,无机材料和复合材料,并对敷料类产品质量控制中出现的问题进行了讨论,展望了敷料类产品的未来发展方向。为医用敷料类产品的研发提供理论依据。     

Investigation of lysine acrylate containing poly(N-isopropylacrylamide) hydrogels as wound dressings in normal and infected wounds

The design of materials for cutaneous wound dressings has advanced from passive wound covers to bioactive materials that promote skin regeneration and prevent infection. Crosslinked poly(N-isopropylacrylamide) (PNIPAAm)-based hydrogels have been investigated for a number of biomedical applications. While these materials can be used for drug delivery, limited cell interactions restrict their biological activity. In this article, acryoyl-lysine (A-Lys) was incorporated into poly(ethylene glycol) crosslinked PNIPAAm to enhance biological activity. A-Lys could be incorporated into the hydrogels to improve cellular interaction in vitro, while maintaining swelling properties and thermoresponsive behavior. Polyhexamethylene biguanide, an antimicrobial agent, could be encapsulated and released from the hydrogels and resulted in decreased bacteria counts within 2 hours. Two in vivo animal wound models were used to evaluate the hydrogel wound dressing. First, application of the hydrogels to a rodent cutaneous wound healing model resulted in significant increase in healing rate when compared with controls. Moreover, the hydrogels were also able to decrease bacteria levels in an infected wound model. These results suggest that PNIPAAm hydrogels containing A-Lys are promising wound dressings due to their ability to promote healing and deliver active antimicrobial drugs to inhibit infection.     

Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds

The injectable polymer scaffolds which are biocompatible and biodegradable are important biomaterials for tissue engineering and drug delivery. Hydrogels derived from natural proteins and polysaccharides are ideal scaffolds for tissue engineering since they resemble the extracellular matrices of the tissue comprised of various amino acids and sugar-based macromolecules. Here, we report a new class of hydrogels derived from oxidized alginate and gelatin. We show that periodate-oxidized sodium alginate having appropriate molecular weight and degree of oxidation rapidly cross-links proteins such as gelatin in the presence of small concentrations of sodium tetraborate (borax) to give injectable systems for tissue engineering, drug delivery and other medical applications. The rapid gelation in the presence of borax is attributed to the slightly alkaline pH of the medium as well as the ability of borax to complex with hydroxyl groups of polysaccharides. The effect of degree of oxidation and concentration of alginate dialdehyde, gelatin and borax on the speed of gelation was examined. As a general rule, the gelling time decreased with increase in concentration of oxidized alginate, gelatin and borax and increase in the degree of oxidation of alginate. Cross-linking parameters of the gel matrix were studied by swelling measurements and trinitrobenzene sulphonic acid (TNBS) assay. In general, the degree of cross-linking was found to increase with increase in the degree of oxidation of alginate, whereas the swelling ratio and the degree of swelling decreased. The gel was found to be biocompatible and biodegradable. The potential of the system as an injectable drug delivery vehicle and as a tissue-engineering scaffold is demonstrated by using primaquine as a model drug and by encapsulation of hepatocytes inside the gel matrix, respectively.     

Development of alginate gel dressing

Alginate-based wound dressing materials have been widely used to promote wound healing and to reduce blood loss from wounds. However, recently a few drawbacks of well-established commercial alginate dressings have been reported. Therefore, we tried to develop a new alginate dressing to reduce the drawbacks. First, four new dressings with different calcium content were prepared, and the cytotoxicity of these four materials, and Kaltostat and Sorbsan, was tested in vitro by culture of fibroblasts with their extracts. Second, full-thickness wounds in pigs were used for the evaluation of wound healing in vivo. Finally, a newly developed alginate dressing was used clinically for treatment of split-thickness skin graft donor sites. The extract medium from ALG3, ALG4, Kaltostat, and Sorbsan induced a significant inhibitory effect on proliferation of fibroblasts. As for wound closure rate, the ALG2-covered wounds had the smallest wound area on day 15. Histologically, foreign-body reaction was least in ALG2-treated wounds. In a clinical study, the main drawback of ALG2 was leakage of wound exudate due to dissolution of the dressing material. However, the transparency of moistened ALG2 allowed easy evaluation of the wound, and after healing it was easy to remove ALG2 from the wound without injury to the reepithelialized skin because ALG2 was relatively nonadherent to the wound.     

新型复合生物抗菌敷料的抗菌强度、吸湿能力及细胞毒性

背景：细菌感染是影响伤口愈合的主要因素之一,伤口渗出液里含有的大量炎症因子、蛋白酶和自由基都会减缓伤口的愈合速度。新型复合生物抗菌敷料的研发对治疗外科感染伤口有重要的意义,是创伤敷料发展的必然趋势。 目的：观察添加纳米银的海藻酸钙敷料的抗菌活性、吸湿能力及细胞毒性。 方法：将纳米银材料添加到海藻酸钙中制备新型复合生物抗菌敷料,并通过使用平板计数法、MTT法、电子显微镜观察法观察敷料的抗菌活性、吸湿能力及细胞毒性,再与银离子海藻酸钙敷料和海藻酸钙敷料进行对比,以期显示出新型复合生物抗菌敷料的具有强抗菌性及低细胞毒性的优势。 结果与结论：与银离子海藻酸钙敷料和海藻酸钙敷料相比,添加纳米银的新型复合生物抗菌敷料对金黄色葡萄球菌、铜绿假单胞菌均有更强的抑菌作用(P < 0.01),细胞毒性较低(P < 0.01);3种敷料的吸湿能力差异无显著性意义。证实此添加纳米银的海藻酸钙敷料的具有强抗菌性及低细胞毒性。      

Synthesis and properties of waterborne polyurethane hydrogels for wound healing dressings

To accomplish ideal wound healing dressing, a series of waterborne polyurethane (WBPU) hydrogels based on polyethylene glycol (PEG) were synthesized by polyaddition reaction in an emulsion system. The stable WBPU hydrogels which have remaining weight of above 85% were obtained. The effect of the soft segment (PEG) content on water absorbability of WBPU hydrogels was investigated. Water absorption % and equilibrium water content (%) of the WBPU hydrogel significantly increased in proportion to PEG content and the time of water-immersion. The maximum water absorption % and equilibrium water content (%) of WBPU hydrogels containing various PEG contents were in the range of 409-810% and 85-96%, respectively. The water vapor transmission rate of the WBPU hydrogels was found to be in the range of 1490-3118 g/m(2)/day. These results suggest that the WBPU hydrogels prepared in this study may have high potential as new wound dressing materials, which provide and maintain the adequate moist environment required to prevent scab formation and dehydration of the wound bed. By the wound healing evaluation using full-thickness rat model experiment, it was found that the wound covered with a typical WBPU hydrogel (HG-78 sample) was completely filled with new epithelium without any significant adverse reactions.     

In vivo evaluation of a novel alginate dressing.

Alginate dressings are currently used in the management of epidermal and dermal wounds, and provide a moist environment that leads to rapid granulation and reepithelialization. However, a cytotoxic effect on proliferation of fibroblasts and residual material with inflammation in healing wounds have been reported recently. We have developed a new alginate dressing (AGA-100), which does not have an inhibitory effect on proliferation of fibroblasts. The purpose of this study was to evaluate the new alginate dressing with respect to wound healing in full- and partial-thickness pig wounds and with respect to biodegradation following implantation into rabbit muscle. Kaltostat and Sorbsan, both well-established commercial dressings, were used as control. The closure rate of full-thickness wounds treated with AGA-100 was significantly higher on day 15 compared with that with Kaltostat and Sorbsan. Reepithelialization rate of partial-thickness wounds treated with Sorbsan was statistically significantly lower on day 3 than those with the other two dressings. As to dressing debris remained in the healing wound, a large amount of foreign debris was noted in all the full-thickness wounds treated with Kaltostat or Sorbsan, while only about one-third of wounds treated with AGA-100 showed a little dressing debris. AGA-100 implanted into the muscle of rabbits was bioresorbed completely within 3 months. Therefore, dressing residue in AGA-100-treated full-thickness wounds might be fully absorbed in a few months. In conclusion, it is shown that our newly developed AGA-100 possesses superior properties compared with typical alginate dressings.     

A genipin-crosslinked gelatin membrane as wound-dressing material: in vitro and in vivo studies

A naturally occurring crosslinking agent (genipin) was used in this study to crosslink gelatin hydrogel to develop a wound-dressing membrane. The study was to investigate the in vitro characteristics of the genipin-crosslinked gelatin membrane. The glutaraldehyde-crosslinked counterpart, at a similar crosslinking degree, was used as control. Additionally, an in vivo experiment was undertaken to study the wound healings covered with the glutaraldehyde- and genipin-crosslinked dressings in a rat model. The in vitro results obtained suggested that crosslinking of gelatin membranes with glutaraldehyde or genipin may produce distinct crosslinking structures. The differences in crosslinking structure can significantly affect the mechanical property, water-vapor-transmission rate, swelling ratio, degradation against enzyme and cellular compatibility of the crosslinked membranes. In the in vivo study, it was found that the degree of inflammatory reaction for the wound treated with the genipin-crosslinked dressing was significantly less severe than that covered with the glutaraldehyde-crosslinked dressing throughout the entire course of the study. Additionally, the healing rate for the wound treated with the genipin-crosslinked dressing was notably faster than its glutaraldehyde-crosslinked counterpart.     

Scanning electron microscopic examination of bacterial immobilisation in a carboxymethyl cellulose (AQUACEL) and alginate dressings

Dressings have been applied to open wounds for centuries. Traditionally they have been absorbent, permeable materials, i.e. gauze that could adhere to desiccated wound surfaces, inducing trauma on removal. With the advent of modern wound care products many dressings are now capable of absorbing large volumes of exudate whilst still continuing to provide a moist wound healing environment. Equally important is their ability to lock exudate in the dressing (i.e. bacterial retention within the dressing matrix) such that upon removal from a wound surface bacterial dispersion is minimised.In these studies detailed scanning electron microscopy techniques have demonstrated the fluid controlling properties of alginate wound dressings and a carboxymethylated cellulose wound dressing (AQUACEL) Hydrofiber) dressing (CMCH)). It was demonstrated that following hydration of the latter wound dressing, the subsequent formation of a cohesive gel was effective in encapsulating large populations of potentially pathogenic bacteria such as Psuedomonas aeruginosa and Staphylococcus aureus under the gelled surface, as well as being immobilised within the swollen fibres. In contrast, hydrated alginate wound dressings did not form a uniform, cohesive gel structure, with the result that fewer bacteria were immobilised within the gel matrix. Many bacteria were trapped on individual, non-hydrated fibres.The unique absorbent gelling properties of the CMCH dressing appears to provide an ideal environment for immobilising bacteria.     

In vitro and in vivo assays on egg white/polyvinyl alcohol/clay nanocomposite hydrogel wound dressings

Novel nanocomposite hydrogel wound dressings on the basis of egg white and polyvinyl alcohol, as matrix, and natural Na-montmorillonite clay, as reinforcing agent, were prepared and their performances on wound healing investigated in vitro and in vivo. In vitro cytotoxicity assay revealed non-cytotoxic activity and excellent biocompatibility level of prepared nanocomposite hydrogel wound dressings. The bacterial penetration assay showed the prepared nanocomposite hydrogel wound dressings are excellent barriers against microorganisms and could protect the wound from infection during the wound healing. In vivo animal study showed that the wound healing process was considerably faster in wounds covered with nanocomposite hydrogel wound dressings compared to the conventional wound dressing, i.e. sterile gauze, due to creation of a moist environment on the wound surface and faster migration rate of the epidermal cells. The mechanical properties of healed wounds with nanocomposite hydrogel wound dressings were better than those control wounds covered with sterile gauze due to their better collagen formation ability as a result of created moist healing condition as well as the presence of egg white, as a source of proteins, in their structures.     

Egg white/poly (vinyl alcohol)/MMT nanocomposite hydrogels for wound dressing

Nanocomposite hydrogels on the basis of egg white and poly (vinyl alcohol) (PVA) containing 0, 5, and 10 wt.% of montmorillonite (MMT) nanoclay were prepared by a facile cyclic freezing–thawing technique and their properties investigated for wound dressing application. The morphological, structural, thermal, physical, and in vitro cytotoxic properties of the prepared nanocomposite hydrogel wound dressings (NHWDs) were experimentally studied. The NHWDs had an exfoliated morphology with a porous structure having pores sizes in the nanometric scale. It was shown that MMT acted as cross-linker in the network of NHWDs and improved their thermal stabilities. The prepared wound dressings were transparent and their equilibrium water contents and water vapor transmission rates, as two important factors of wound dressings, were very close to the properties of human skin which means that the prepared wound dressings could interact appropriately with the damaged tissues of wounds and protect them like an artificial skin during the wound healing process. The in vitro cytotoxicity assay also confirmed the non-cytotoxic nature of the prepared NHWDs. It was finally concluded that the prepared egg white/PVA/MMT nanocomposite hydrogels are promising materials to be used as novel wound dressings in wound and burn care.     

新型医用敷料的分类及特点

背景：临床应用的多种新型创面敷料可加速创面修复,减少伤口感染,提高治愈率,缩短病程,减轻患者痛苦。 目的：回顾传统医用敷料及新型医用敷料的优缺点,展望新型医用敷料的临床应用及发展。 方法：应用计算机检索2003年1月至2006年8月PubMed数据库及2000年1月至2006年8月CNKI数据库有关医用敷料种类、特点及临床应用的研究,检索词为“Medical dressing,医用敷料”。 结果与结论：医用新型敷料分为薄膜类、水凝胶类、藻酸盐类、泡沫类、水胶体类、药用类敷料。薄膜类敷料透明,便于观察伤口,能密切黏附于创面表面,有效保持创面渗出液,提供有利于创面愈合的湿润环境,促使坏死组织脱落,减轻创面疼痛会,缺点为吸水性能欠佳。水凝胶类敷料能与不平整的创面紧密粘合,减少细菌滋生,加速新生血管生成,促进上皮细胞生长。水胶体类敷料比薄膜类敷料厚许多,胶层的厚度决定其吸收能力的大小,水胶体敷料可吸收少量到中量渗液,不适用于渗出液多的创面。泡沫类敷料具有多孔性,表面张力低,富有弹性,可塑性强、轻便,对渗出液的吸收力强,对氧气及二氧化碳几乎完全通透,可作为药物载体。新型藻酸盐类敷料比较柔软,容易折叠,敷贴方便,在创面上形成柔软类似凝胶的半固体物质,为创面提供一个湿润环境,提高表皮细胞的再生能力,加快表皮细胞移动。药用类敷料有保护创面、止痛、止血、消炎、促进新生肉芽组织及上皮细胞生长,加速创面愈合等功能。     

Single and dual crosslinked oxidized methacrylated alginate/PEG hydrogels for bioadhesive applications

A degradable, cytocompatible bioadhesive can facilitate surgical procedures and minimize patient pain and post-surgical complications. In this study a bioadhesive hydrogel system based on oxidized methacrylated alginate/8-arm poly(ethylene glycol) amine (OMA/PEG) has been developed, and the bioadhesive characteristics of the crosslinked OMA/PEG hydrogels evaluated. Here we demonstrate that the swelling behavior, degradation profiles, and storage moduli of crosslinked OMA/PEG hydrogels are tunable by varying the degree of alginate oxidation. The crosslinked OMA/PEG hydrogels exhibit cytocompatibility when cultured with human bone marrow-derived mesenchymal stem cells. In addition, the adhesion strength of these hydrogels, controllable by varying the alginate oxidation level and measured using a porcine skin model, is superior to commercially available fibrin glue. This OMA/PEG hydrogel system with controllable biodegradation and mechanical properties and adhesion strength may be a promising bioadhesive for clinical use in biomedical applications, such as drug delivery, wound closure and healing, biomedical device implantation, and tissue engineering.     

Performance of an in situ formed bioactive hydrogel dressing from a PEG-based hyperbranched multifunctional copolymer

Hydrogel dressings have been widely used for wound management due to their ability to maintain a hydrated wound environment, restore the skin’s physical barrier and facilitate regular dressing replacement. However, the therapeutic functions of standard hydrogel dressings are restricted. In this study, an injectable hybrid hydrogel dressing system was prepared from a polyethylene glycol (PEG)-based thermoresponsive hyperbranched multiacrylate functional copolymer and thiol-modified hyaluronic acid in combination with adipose-derived stem cells (ADSCs). The cell viability, proliferation and metabolic activity of the encapsulated ADSCs were studied in vitro, and a rat dorsal full-thickness wound model was used to evaluate this bioactive hydrogel dressing in vivo. It was found that long-term cell viability could be achieved for both in vitro (21 days) and in vivo (14 days) studies. With ADSCs, this hydrogel system prevented wound contraction and enhanced angiogenesis, showing the potential of this system as a bioactive hydrogel dressing for wound healing.     

Self-crosslinked oxidized alginate/gelatin hydrogel as injectable,adhesive biomimetic scaffolds for cartilage regeneration

Biopolymeric hydrogels that mimic the properties of extracellular matrix have great potential in promoting cellular migration and proliferation for tissue regeneration. The authors reported earlier that rapidly gelling, biodegradable, injectable hydrogels can be prepared by self-crosslinking of periodate oxidized alginate and gelatin in the presence of borax, without using any toxic crosslinking agents. The present paper investigates the suitability of this hydrogel as a minimally invasive injectable, cell-attractive and adhesive scaffold for cartilage tissue engineering for the treatment of osteoarthritis. Time and frequency sweep rheology analysis confirmed gel formation within 20 s. The hydrogel integrated well with the cartilage tissue, with a burst pressure of 70 ± 3 mmHg, indicating its adhesive nature. Hydrogel induced negligible inflammatory and oxidative stress responses, a prerequisite for the management and treatment of osteoarthritis. Scanning electron microscopy images of primary murine chondrocytes encapsulated within the matrix revealed attachment of cells onto the hydrogel matrix. Chondrocytes demonstrated viability, proliferation and migration within the matrix, while maintaining their phenotype, as seen by expression of collagen type II and aggrecan, and functionality, as seen by enhanced glycosoaminoglycan (GAG) deposition with time. DNA content and GAG deposition of chondrocytes within the matrix can be tuned by incorporation of bioactive signaling molecules such as dexamethasone, chondroitin sulphate, platelet derived growth factor (PDGF-BB) and combination of these three agents. The results suggest that self-crosslinked oxidized alginate/gelatin hydrogel may be a promising injectable, cell-attracting adhesive matrix for neo-cartilage formation in the management and treatment of osteoarthritis.     

In Situ Gelable Glycation-Resistant Hydrogels Composed of Gelatin and Oxidized Alginate

An in situ gelable glycation-resistant hydrogel has been prepared from oxidized alginate (Oalg) and gelatin. Aminoguanidine, an effective inhibitor of the glycation reaction, was first encapsulated in gelatin microspheres followed by incorporation into the hydrogel. The gelation process was monitored rheologically, and the results showed that the AMG-loaded Oalg/gelatin system solidified quickly at body temperature. Moreover, the hydrogels were highly porous, and the AMG-loaded microspheres dispersed in the hydrogels remained intact. Hydrogels' AMG loadings did not appear to change their degradation behaviors. AMG could be released from the hydrogels in a sustainable manner for a relatively short duration. Incorporation of AMG into the hydrogels resulted in imparting a glycation-resistant capability. Lastly, long-term in vitro incubation of all hydrogel formulations with fibroblasts did not reveal any cytotoxic potential.     

联合应用藻酸盐和聚亚安酯敷料促进中厚皮供区创面愈合的临床观察

目的探讨联合应用藻酸盐和自粘型聚亚安酯敷料于中厚皮片供皮区,加速创面愈合的方法。方法烧伤后瘢痕整形中厚皮取皮术后,实验组19例以藻酸盐和自粘型聚亚安酯敷料顺序联合应用覆盖供皮区创面,对照组17例以传统的凡士林纱布加棉垫绷带加压包扎供皮区创面,受术者于术后第1天、第2天及第10天揭除敷料时就供皮区疼痛程度按疼痛视觉模拟评分,并对敷料对术后活动的影响、术后10d揭除敷料难易程度进行评价,记录两组供皮区创面愈合的时间。结果术后第1天、第2天及术后第10天揭除敷料时,实验组受术者的疼痛视觉模拟评分低于对照组,实验组中36.8%受术者术后活动不受限,高于对照组（P〈0.05）;术后10d,实验组揭除敷料更为容易,且实验组供皮区愈合时间平均为9.8d,短于对照组（P〈0.01）。结论藻酸盐敷料和聚亚安酯敷料联合应用于中厚皮片供皮区,具有降低术后疼痛,减轻术后活动不便,操作方便,缩短供皮区愈合时间的优点,值得临床推广应用。     

基于天然衍生多糖和蛋白质的促伤口愈合水凝胶

伤口愈合是一种常见的生理过程,在组织病变开始后,一系列分子和细胞事件发生以重建身体和外部环境之间的屏障。水凝胶在伤口治疗中具有显著优势,它们能够对伤口愈合过程进行时空控制,有效促进受损组织在水合环境下愈合。多糖和蛋白质的各种突出特征可用做制备仿生多功能水凝胶的有效伤口敷料。结合生物小分子和支持细胞,水凝胶可以进一步发挥更快和更好的愈合功能。本综述主要讨论了天然衍生多糖和蛋白质水凝胶伤口敷料对创面病理生理学的影响, 及其理想特性、交联机制和制造技术。