可注射性胶原生物材料的安全性评价

研究可注射性胶原生物材料的急性毒性和三项致突变性作用.测定小鼠经口、经腹腔注射急性毒性试验LD50＞10000mg/kg.小鼠骨髓细胞微核试验、小鼠睾丸初级精母细胞染色体畸变试验和Ames试验均为阴性.说明可注射性胶原对小鼠急性毒性低,且不具有致突变作用.临床上可试作为组织填充剂,具有较大的安全性和可靠性.     

小鼠Ⅱ型胶原性关节炎模型的制备

目的　制备Ⅱ型胶原诱发的小鼠关节炎模型。方法　利用Ⅱ型胶原乳剂皮内注射。结果　与对照组比较,Ⅱ型胶原性关节组小鼠的足爪肿胀和关节评分明显增加,并且Ⅱ型胶原诱发的迟发性变态反应呈阳性,血清中也检测出抗Ⅱ型胶原的抗体。结论　Ⅱ型胶原乳剂皮内注射可制备关节炎小鼠模型。     

肝脏注射促肝细胞生长素和地塞米松对肝硬化肝窦病变及Ⅳ型胶原表达的影响

目的观察肝脏注射促肝细胞生长素和地塞米松对肝硬化肝窦组织病变的体视学改变及肝窦Ⅳ型胶原表达的影响。方法在超声引导下,对98例肝硬化患者肝脏注射促肝细胞生长素80mg及地塞米松1mg,每周注射2次,12次为一疗程,治疗1个疗程后,通过肝脏穿刺活检病理观察肝窦组织病变变化情况及Ⅳ型胶原的表达情况。结果98例肝硬化患者治疗1个疗程后,肝窦组织病变明显改善（P〈0．01）,Ⅳ型胶原表达显著减弱（P〈0．01）。结论对肝硬化患者行超声引导下肝脏注射促肝细胞生长素和地塞米松能明显改善肝窦组织病变及Ⅳ型胶原的表达。     

Ⅲ型和V型胶原的制备及其结构研究

目的 从牛真皮和角膜分别制备Ⅲ型和V型胶原，检测制备过程，分析胶原的结构特征。方法 提取在含蛋白酶的乙酸溶液中进行，分离采用不同浓度的氯化钠溶液进行盐析和透析；电泳分析胶原的制备过程和结构特征。结果 一些V型胶原分子可能存在二硫键结构，而每条Ⅲ型胶原分子的末端肽链均有二硫键结构。结论 酶解、盐析和透析法可使Ⅲ型或V型胶原从组织中分离出来。     

水飞蓟宾卵磷脂复合物对肝纤维化大鼠肝脏中胶原表达的影响

目的：应用二甲基亚硝胺（DMN）建立肝纤维化大鼠模型，研究水飞蓟宾卵磷脂复合物（SPC）对纤维化肝组织中Ⅰ、Ⅲ型胶原表达的影响。方法：60只大鼠随机分为正常组、模型组、SPC干预组、对照组及SPC治疗组。采用DMN腹腔内注射的方法建立肝纤维化大鼠模型。按6期分类法评价各组肝纤维化程度。应用RT-PCR检测各组肝组织中Ⅰ、Ⅲ型胶原mRNA水平；应用免疫组织化学技术检测各组动物肝组织Ⅰ、Ⅲ型胶原的表达。结果：SPC干预组与治疗组的大鼠肝纤维化程度、肝组织中Ⅰ型与Ⅲ型胶原㈣水平及肝组织中Ⅰ型与Ⅲ型胶原的阳性表达均分别较模型组与模型对照组显著减轻与下降。结论：SPC能明显减轻肝组织病理改变和肝纤维化程度，抑制Ⅰ、Ⅲ胶原的表达是其抗肝纤维化的机制之一。     

扩张型心肌病动物模型的建立及实验室研究

目的：观察阿霉素建立扩张型心肌病（dilated cardiomyopathy,DCM）动物模型后,大鼠心肌细胞及血浆纤维蛋白的变化。方法：7周龄雄性SD大鼠阿霉素腹腔注射建立大鼠扩张型心肌病模型。观察DCM组SD大鼠与正常对照组超声心动图的改变,并对DCM大鼠心肌组织的病理改变及血浆中I型前胶原羧基端肽（PICP）、Ⅲ型前胶原氨基端肽（PIIINP）的浓度进行评估。结果：与正常对照组相比,DCM组心腔明显扩张,左室舒张期末内径（LVED）、左室收缩期末内径（LVES）明显增加;左室内径缩短率（FS）及左室射血分数（LVEF）明显降低。与正常对照组相比,DCM组血浆中的PICP、PⅢNP的浓度明显升高,差异具有统计学意义（P〈0．01]。结论：用腹腔注射阿霉素可成功复制DCM大鼠模型,且在DCM发生发展过程中心肌发生了纤维化。     

慢性乙型病毒性肝炎病理组织学与血清纤维化指标关系的探讨

报告４６例慢性乙型病毒性肝炎组织病理学与血清的纤维化指标－Ⅰ型胶原，Ⅲ型前胶原太测定的阳性率并进行比较。结果：血清Ⅰ型胶原和ＰⅢＰ分别与组织Ⅰ型，Ⅲ型胶原阳性率比较，差别均无显著性，ｘ＾２分别为０．８０６２，１．２１０５，Ｐ均〉０．０５。表明血清Ｉ型胶原与ＰⅢＰ含量的观察可作为一项判断早期肝纤维化的良好指标。     

Ⅲ型和Ⅴ型胶原的制备及其结构研究

目的从牛真皮和角膜分别制备Ⅲ型和Ⅴ型胶原 ,检测制备过程 ,分析胶原的结构特征。方法提取在含蛋白酶的乙酸溶液中进行 ,分离采用不同浓度的氯化钠溶液进行盐析和透析 ;电泳分析胶原的制备过程和结构特征。结果一些Ⅴ型胶原分子可能存在二硫键结构 ,而每条Ⅲ型胶原分子的末端肽链均有二硫键结构。结论酶解、盐析和透析法可使Ⅲ型或Ⅴ型胶原从组织中分离出来     

慢性肾功能衰竭患者血清Ⅳ型胶原水平的变化及意义

目的 探讨慢性肾功能衰竭血清Ⅳ型胶原的变化及意义。方法 采用放射名疫法对84例经临床上诊断为慢性肾功能衰竭患者及45例正常人血清Ⅳ型胶原水平进行检测。结果 慢性肾功能衰竭氮质血症期患者血清Ⅳ型胶原水平与正常对照组相比无统计学意义；慢性肾功能衰竭期及尿毒症期血清Ⅳ型胶原水平明显高于正常对照组，结论 血清Ⅳ型胶原水平可反映肾脏损害的程度，常规检测血清Ⅳ型胶原水平，可作为一项辅助，无创伤性检测慢性肾功能衰竭病情进展的较敏感的指标。     

胶原海绵联合地塞米松预防大鼠椎板切除后硬膜瘢痕粘连的研究

目的 评价不同硬膜外覆盖物以及局部应用类固醇激素对腰椎术后瘢痕形成的影响,并初步探讨其机制.方法 Wistar大鼠80只随机数字表法分为4组:胶原海绵十地塞米松组、胶原海绵组、明胶海绵组和对照组(无任何硬脊膜外覆盖物),每组实验动物20只,麻醉后在背部正中做切口行L1-L5全椎板切除,造成0.5 cm×1.0 cm骨性缺损,显露硬膜.胶原海绵十地塞米松组动物硬膜外放置胶原海绵并注射0.1 mL地塞米松,胶原海绵组动物硬膜外放置胶原海绵,明胶海绵组动物硬膜外放置明胶海绵,对照组直接缝合肌肉组织.手术后12周重新切开伤口,观察硬膜外瘢痕形成及与硬脊膜粘连情况.应用免疫组化和Western blot检测显示硬膜外瘢痕及周围组织中TGF-β1、VEGF表达情况,比较各组间差异.结果 肉眼及光镜观察胶原海绵十地塞米松组和胶原海绵组的硬膜外瘢痕粘连明显少于明胶海绵组和对照组,而胶原海绵十地塞米松组与胶原海绵组之间无显著差异,明胶海绵组与对照组间无显著差异;免疫组化及Western blot检测显示胶原海绵十地塞米松组和胶原海绵组硬膜外瘢痕及周围组织中TGF-β1、VEGF的表达显著少于明胶海绵组和对照组,而胶原海绵+地塞米松组与胶原海绵组之间、明胶海绵组与对照组之间均无明显差异.结论 胶原海绵可以显著降低实验大鼠腰椎术后硬膜周围瘢痕增生粘连的形成,同时加用局部注射地塞米松并没有加强这种作用;局部应用明胶海绵不能减少硬膜外瘢痕增生粘连的形成.胶原海绵应用后局部的TGF-β1和VEGF的低表达可能是减少硬膜外瘢痕增生粘连的重要机制之一.     

Injectable matrices and scaffolds for drug delivery in tissue engineering

Injectable matrices and depots have been the subject of much research in the field of drug delivery. The classical tissue engineering paradigm includes a matrix or scaffold to facilitate tissue growth and provide structural support, cells, and the delivery of bioactive molecules. As both tissue engineering and drug delivery techniques benefit from the use of injectable materials due to the minimal invasiveness of an injection, significant crossover should be observed between injectable materials in both fields. This review aims to outline injectable materials and processing techniques used in both tissue engineering and drug delivery and to describe methods by which current injectable materials in the field of drug delivery can be adapted for use as injectable scaffolds for tissue engineering.     

Collagen gel systems for sustained delivery and tissue engineering

Collagen gels are flowable, suggesting the possibility of an easily injectable, biocompatible drug delivery matrix. Sustained release of therapeutic molecules from collagen matrices, however, is beset with difficulties. Fibrillar collagen gels have an effective pore size of several tens of nanometers, too large to control release by hindered diffusion. To control release, it is necessary to rely on binding of the active agent to collagen, either by covalent or non-covalent bonds, or on sequestering in a secondary matrix. Such steps rapidly increase the complexity of the system. Non-fibrillar collagen has a lower effective pore size (4-6 nm), but it dissolves rapidly in vivo (approximately 24 h). For tissue engineering applications, collagen gels are more attractive, since they can act as a "cage" to retain cells or as gene delivery complexes, which are larger than drugs and therapeutic proteins. The gels have limitations in terms of strength, but reinforcement with solid components and alignment during gelation and culture can improve performance.     

Cisplatin/epinephrine injectable gel.

1. Cisplatin/epinephrine injectable gel is a preparation for intratumoural injection containing cisplatin 4 mg/ml, epinephrine (adrenaline) 0.1 mg/ml and bovine collagen as a protein carrier matrix. It has been evaluated for the palliative treatment of accessible inoperable metastatic or recurrent solid tumours. 2. The vasoconstrictor action of epinephrine limits the diffusion of cisplatin into the systemic circulation. Intratumoural injection of cisplatin/epinephrine injectable gel achieves high concentrations of cisplatin in the tumour with very low concentrations in plasma and other tissues. 3. In double-blind randomised trials, cisplatin/epinephrine injectable gel was more efficacious than placebo in the palliative treatment of recurrent and resistant head and neck squamous cell carcinoma. 4. Cisplatin/epinephrine injectable gel reduced tumour size and improved local symptoms in patients with metastatic breast cancer, metastatic malignant melanoma, oesophageal carcinoma and hepatic tumours in a number of noncomparative clinical trials. 5. Adverse events with the use of cisplatin/epinephrine injectable gel are mainly limited to the local site of injection. No systemic adverse events such as nephrotoxicity, neurotoxicity or ototoxicity have been reported with use of this preparation.     

Thermo-responsive injectable naringin-loaded hydrogel polymerised sodium alginate/bioglass delivery for articular cartilage

In the human body, joint cartilage is of great importance. It has long been a big therapeutic problem to fix joint cartilage lesions as it appears due to different conditions. Recent stories have shown that the cartilage replacement process must delay the extracellular (ECM) cartilage deterioration and modulate the host''s inflammation response. For the reconstruction of the articular cartilage, drug-loaded injectable hydrogels were developed. This hydrogel could retain the chondrocyte phenotype, but the host''s inflammatory reaction could also be controlled. The bioglass (BG)/sodium alginate (SA) injectable hydrogels was combined with agarose (AG)/Naringin hydrogel in injectable thermal response for articular cartilage regeneration with a non-chargeable hydrogel that contains both Naringin and BG (Naringin–BG hydrogels). The Naringin–BG hydrogel has an adequate swelling ratio that encourages the fusion of tissue formed with host tissue and enables the gradual release of Naringin bioavailabilities enhanced in situ. The Naringin–BG hydrogel can upgrade the typical chondrocyte phenotype by upregulating aggrecan, SRY-box 9, and collagen type II alpha one chain. It may also stimulate the polarization of M2 macrophage, lower inflammations, and prevent ECM degradations through the decrease of the expressions of the indictable metalloproteinase-13 matrix, nitric oxide synthase, and metalloproteinase-1 matrix. The formed tissues were identical to normal tissues and firmly incorporated with the surrounding tissue after administering the Naringin–BG hydrogels into the rat model articular cartilage defects. Then the injectable Naringin–BG hydrogel increases the bioavailable content of Naringin and retains the chondrocyte phenotype.     

Polyhydroxyalkanonate derivatives in current clinical applications and trials

Polyhydroxyalkanonate is a typical biodegradable material, which is permitted for use in the medical and pharmaceutical fields. For its biodegradability, biocompatibility, and toxicological safety, the majority of products practically used are composed of homo-polymers of poly(lactic acid), poly(glycolic acid), and poly(epsilon-caprolactone) and their co-polymers. On the market, suture strings are still the main usage. The needs of biodegradable materials have been being gradually increased by the development of drug delivery systems, tissue engineering, and regenerative medicine. Some types of formulation, that is, mono-fibers, twisted fibers, films, fabrics, sponges, and injectable particles are developed to match each purpose. This article reviews the current clinical applications and trials of polyhydroxyalcanonate products.     

注射用利培酮微球的作用机制及临床应用

注射用利培酮微球是第一个非典型抗精神病药长效剂型,于2006年进入我国市场。它采用先进的Med isorb(微球体)专利技术,减少了首过效应,提高了生物利用度,减少了吸收和生物代谢的个体差异;其在体内缓慢均匀释放的特性,使患者能保持稳定的稳态血浆药物浓度,即便长期治疗中漏掉1次注射,体内药物也不会突然中断;该药物临床疗效好、不良反应少、安全性高,使患者有较好的依从性,且具有最佳的成本-疗效效益。文中综述了注射用利培酮微球的药动学、药效学、临床疗效、安全性及药物经济学效益的最新研究进展。     

Poly-L-lactic acid: an overview

In August 2004, the US Food and Drug Administration approved a poly-L-lactic acid (PLLA)-based injectable medical device for restoration and/or correction of the signs of facial fat loss (lipoatrophy) in people with human immunodeficiency virus. As a result, the properties of the PLLA microparticles have received considerable interest from the medical community. Polylactides have a long-standing history of safe use in medical applications, such as pins, plates, screws, intra-bone and soft-tissue implants, and as vectors for sustained release of bioactive compounds. The L-isomer of polylactic acid is a biodegradable, biocompatible, biologically inert, synthetic polymer. Putatively, PLLA microparticles initiate neocollagenesis as a result of a normal foreign-body reaction to their presence. The build-up of collagen over time creates volume at the site of injection, while the PLLA microparticles are metabolized to carbon dioxide and water and expelled through the respiratory system.     

Chitosan-thioglycolic acid conjugate: a new scaffold material for tissue engineering?

It was the aim of this study to evaluate chitosan-thioglycolic acid (chitosan-TGA) conjugate as scaffold material in tissue engineering. Chitosan was modified by the introduction of thiol groups. Briefly, TGA was introduced to chitosan via amide bond formation mediated by a carbodiimide. The properties of the resulting polymer were thereby altered in regard to water solubility, mucoadhesion, biodegradability and in situ gelling compared to the original polymer. Due to the immobilised thiol groups (240+/-30 micromol thiol groups per gram polymer), the viscosity of a 1.5% chitosan-TGA solution was improved 4.3-fold. This can be explained by the formation of disulphide bonds within this polymeric network. The conjugate was tested as scaffold material in form of a gel and sheets. Furthermore, the influence of the thiol groups on the viability of L-929 mouse fibroblasts was evaluated. It was shown that the L-929 mouse fibroblasts grew on both scaffolds despite the thiol groups, although the different surface conditions seemed to have an influence on the growing rate. Chitosan-TGA sheets seemed to be the more preferred layer. The improved in situ gelling may be important for ongoing developments. Direct injectable matrices at the site of tissue damage mimicking the tissue being restored may be a future trend on this topic. Hence, chitosan-TGA is a promising candidate as scaffold material in tissue engineering.     

Tissue engineered buccal mucosa for urethroplasty: Progress and future directions

PurposeAutologous buccal mucosa is commonly utilized in the surgical treatment of urethral strictures. Extensive strictures require a larger quantity of tissue, which may lead to donor site morbidity. This review assesses progress in producing tissue engineered buccal mucosa as an alternative graft material.ResultsFew clinical studies have introduced cells onto biological or synthetic scaffolds and implanted resulting constructs in patients. The available studies show that buccal mucosa cells on acellular human dermis or on collagen matrix lead to good acute stage tissue integration. Urothelial cells on a synthetic substrate also perform well. However while some patients do well many years post-grafting, others develop stricture recurrence. Acellular biomaterials used to treat long urethral defects in animals commonly lead to fibrosis.ConclusionsTissue engineered buccal mucosa shows promise as a substitute for native tissue. The fibrosis which occurs months post-implantation may reflect the underlying disease process recurring in these patients.     

Injectable in situ forming drug delivery system for cancer chemotherapy using a novel tissue adhesive: characterization and in vitro evaluation.

Injectable polymers that are biocompatible and biodegradable are important biomaterials for drug delivery system (DDS) and tissue engineering. We have already developed novel tissue adhesives consisting of biomacromolecules and organic acid derivatives with active ester groups. The resulting tissue adhesive forms in situ as a gel and has high bonding strength for living tissue as well as it has good biocompatibility and biodegradability. Here, we report on the physicochemical properties and in vitro evaluation of this novel tissue adhesive consisting of human serum albumin (HSA) and tartaric acid derivative (TAD) containing doxorubicin hydrochloride (DOX). The results of the measurement of physicochemical characteristics indicate that the gelation time and gel strength of HSA-TAD gels can be controlled according to the material composition. The bonding strength of HSA-TAD adhesives was found to be sufficient to adhere at focus and to correspond with the cross-linking density of HSA-TAD gels. Furthermore, the release of DOX from HSA-TAD gels was sustained for approximately 100 h in an in vitro evaluation. The novel tissue adhesive, therefore, is expected to be applicable for use as an injectable in situ forming DDS.