Biodegradable Polydioxanone Microspheres for Transcatheter Arterial Embolization: Proof of Principle

PurposeTo evaluate feasibility, embolization success, biodegradability, reperfusion, and biocompatibility of biodegradable microspheres (MS) made from polydioxanone (PDO) for transcatheter arterial embolization.Materials and MethodsUnilateral selective renal embolization of a segmental artery was performed in 16 New Zealand White rabbits with PDO-MS (100–150 μm and 90–315 μm). Animals were randomly assigned to different observation periods and underwent control digital subtraction angiography (DSA) and MR imaging immediately (n = 3), 1 week (n = 2), 4 weeks (n = 2), 8 weeks (n = 2), 12 weeks (n = 5), and 16 weeks (n = 2) after embolization. Kidneys were harvested for macroscopic and histologic analysis of embolization success, biodegradability, and biocompatibility.ResultsEmbolization was technically successful in 15 of 16 animals. One animal died of anesthesia-related circulatory failure. The 100–150 μm MS were injected easily through 3-F catheters; the 90–315 μm MS tended to clog with intermittent catheter obstruction. DSA and MR imaging showed successful target embolization in 13 of 15 animals. In 2 animals, the entire kidney was affected owing to catheter clogging, including a reflux of MS while flushing. Control DSA and MR imaging showed increasing vascular reperfusion with time. Macroscopic and histologic analysis revealed necrosis/infarction in areas in which embolization was achieved. MS were extensively degraded after 16 weeks, and overall inflammatory reaction was mild.ConclusionsBiodegradable PDO-MS induced effective embolization of target vessels while demonstrating good biocompatibility. MS increasingly dissolved at 16 weeks, partial reperfusion started at week 1, and complete reperfusion started at week 8, thus offering possible advantages as a temporary embolic agent.     

Poly-lactic acid and agarose gelatin play an active role in the recovery of spinal cord injury

Objective To investigate the role of poly-lactic acid and agarose gelatin in promoting the functional recovery of the injured spinal cord. Methods Poly-lactic acid ( PLA) or agarose was embedded in the space between two stumps of the hemisectioned spinal cord. Immunohistochemistry was used to show astroglia proliferation and the infiltration of RhoA-positive cells. Locomotor activity recovery was evaluated by testing the function of hindlimbs. Results Astrogli-as and RhoA labeled non-neuronal cells accumulated in the area adjacent to the implant, while the number of RhoA-positive cells was decreased dramatically in the absence of implant. Animals implanted with agarose gelatin recovered more quickly than those with PLA, concomitant with a higher survival rate of the neurons. Conclusion Both PLA and agarose gelatin benefited the recovery of spinal cord after injury by providing a scaffold for astroglia processes. Modulation of the rigidity, pore size and inner structure of PLA and agarose gelatin might make these biodegradable materials more effective in the regeneration of the central nervous system (CNS).     

异种骨基质明胶(BMG)诱导成骨活性的实验研究

本文按着 Urist 方法制备了人、兔、猪和羊四种骨基质明胶(BMG),分别将其植入25只成年 SD 大鼠的胸部和股部肌肉,在手术的第2、4、6和8周后,通过光学显微镜观察各种 BMG 在肌肉内的免疫排斥反应和诱导成骨活性。结果表明:异种 BMG 具有一定的诱导成骨能力。但在 BMG 周围亦出现程度不同的排斥反应。本文认为,进一步降低 BMG 的抗原性,提高其诱导成骨活性,对于异种 BMG的临床应用将具有重要意义。     

Improvement in Wound Healing by Epidermal Growth Factor (EGF) Ointment. I. Effect of Nafamostat,Gabexate, or Gelatin on Stabilization and Efficacy of EGF

The healing effect of human epidermal growth factor (hEGF) on open wounds was studied in rats. No improvement in wound healing was found by topical application of EGF alone to open wound sites. We found an ointment containing EGF and a protease inhibitor, nafamostat mesilate or gabexate mesilate, or gelatin accelerated the healing rate of open wounds. Significant increases in the dry weight of the wound site granulation tissue, uronic acid (as an index of acid mucopolysaccharide) and hydroxyproline (as an index of collagen) were observed by treatment with EGF ointment containing nafamostat compared with the controls. The effects of the protease inhibitor on wound healing were dose dependent. Nafamostat was more efficient than gabexate or gelatin on wound healing. The degradation of ¹²⁵I-EGF in wound tissue homogenate was significantly decreased in the presence of a protease inhibitor, such as nafamostat or gabexate, or gelatin. These findings indicate that the stabilization of EGF at the wound site is an important factor in permitting the expression of its healing effects and suggest that the ointment containing EGF and a stabilizing agent would be a suitable dosage form for acceleration of wound repair.     

阿霉素磁性明胶微球的研究

报告了阿霉素磁性明胶微球（Ａｄｒ－ＭＧ－ｍｓ）的制备与性质，研究了超细氧化铁粒子的合成和磁性明胶微球（ＭＧ－ｍｓ）在狗体内的栓塞效果。阿霉素磁性明胶微球由２％阿霉素（Ａｄｒ）、６８％明胶和３０％的磁铁粒子组成，微球的平均粒径为２２μｍ。在体外实验中，药物释放速度证明微球有缓释的性质。磁铁粒子的平均粒径约为１０ｎｍ，磁性明胶微球与￣（９９ｍ）Ｔｃ标记磁性明胶微球通过导管分别输入狗的肝动脉内进行栓塞，照相和血管造影显示在未加外磁场时磁性明胶微球在左右肝叶分布几乎相等，而在１２００高斯的外磁场作用下，靶部位肝左叶的微球分布是肝右叶的２．２５倍，而甲状腺、脑、心脏的微球很微量，结果表明磁性明胶微球在外磁场作用下是一个很好的治疗肝癌的栓塞剂。     

人表皮生长因子与碱性成纤维细胞生长因子纳米缓释剂对成纤维细胞的影响

目的:制备碱性成纤维细胞生长因子(bFGF)、人表皮生长因子(EGF)可降解缓释微球,考察其生物活性的保存情况,以及它们对成纤维细胞的作用。方法:采用改良的乳化冷凝法交联制备复合bFGF、EGF的明胶缓释微球,将它们加入成纤维细胞的培养液中,用细胞计数法、四甲基偶氮唑盐微量反应比色法(MTT法)测定细胞增殖情况。结果:复合bFGF、EGF的缓释微球平均粒径(11.32±3.64)μm;培养1天后各组细胞计数、吸光度(A)值差异均无显著性;5天后,两种生长因子缓释微球组细胞计数、吸光度(A)值明显高于对照组;7天后,两种生长因子缓释微球组值仍高于其它组,但差异无显著性。结论:复合bFGF、EGF的缓释微球制备工艺简便,成球性好;能较长时间地持续释放活性bFGF、EGF,可促进成纤维细胞的增殖。     

Transcatheter arterial embolization of abnormal neovessels in a swine model of knee arthritis

BackgroundIn recent years, transcatheter arterial embolization (TAE) using imipenem/cilastatin (IPM/CS) has attracted attention as a treatment for relieving osteoarthritis (OA) pain. However, IPM/CS is not approved by Japanese medical insurance for use as an embolic material. Therefore, it is necessary to develop new embolic materials for TAE to relieve OA pain. The purpose of this study was to develop a swine model of knee arthritis and embolize abnormal neovessels (ANs) using two different embolic materials. We compared the embolic effects and tissue damage in knees.MethodsKnee arthritis was induced by intra-articular injection of papain into 12 knees in six female swine. The swine were divided into two groups of three swine each (six knees per group) for embolization of ANs in the knees with either IPM/CS or soluble gelatin sponge particles (SGSs). Three days after embolization, we compared the embolic effects using angiography and the tissue damage histopathologically.ResultsANs were observed in all 12 knees at 42 days after papain injection. The ANs disappeared and the patent arteries were recanalized 3 days after TAE in all 12 knees. Histopathological evaluation revealed synovitis changes, such as synovial thickening and inflammatory cell infiltration, in all 12 knees. There was no evidence of skin or muscle necrosis in either group. The appearance of ANs, recanalization of the parent arteries, and histopathological outcomes were not significantly different between the two groups.ConclusionSGSs were as safe as IPM/CS for TAE of ANs in this swine model of knee arthritis.     

同种与异种骨基质明胶修复颅骨缺损的实验研究

以家兔颅顶骨直径１０ｍｍ园形骨缺损作为动物模型，分别植入同种（兔）、异种（人、猪、羊）的骨基质明胶。植入后４、８、１２、１６ｗ进行ｘ线摄片和组织学检查。结果显示，同种骨基质明胶无免疫排斥反应，具有良好的骨诱导作用，术后１２ｗ骨缺损完全修复；异种骨基质明胶植入早期，存在着不同程度的排斥反应，植骨后期（１２～１６ｗ），随着排斥反应的减轻，亦出现了诱导成骨。结果说明，如能改进异种骨基质明胶的制作方法，降低其抗原性，将具有重要的临床应用价值。     

Induction of immunoglobulin-producing human peripheral blood lymphocytes in serum-free medium

Induction of immunoglobulin-secreting cells from human peripheral blood lymphocytes in a serum-free culture medium was studied. Albumin, transferrin, insulin and fibronectin can replace serum entirely for support of pokeweed mitogen (PWM)-stimulated B lymphocytes, measured by a reverse hemolytic plaque assay using protein A-coated red cells. In this serum-free system, growth and maturation to IgM and IgG secretion occur at the same or higher efficiency as in conventional serum-containing medium, with maximum numbers of plaque-forming cells on day 6 at optimal dose of PWM, 0.5 ～ 5 μg/ml. This system can be used to avoid the interference from undefined serum components.     

急性超容血液稀释对血流动力学的影响

目的 观察不同人工胶体液行急性超容血液稀释(AHHD)对血流动力学的影响.方法 45例ASA Ⅰ～Ⅱ级腹部手术患者,随机分为3组:对照组(C组)、6%羟乙基淀粉组(H组)及4%琥珀酰明胶组(G组).在麻醉诱导后开始输液或扩容:C组输入林格液15 ml/kg,H、G组输入林格液15 ml/kg和胶体液20 ml/kg,均在40 min内完成.监测3组术前、麻醉诱导后、输液或扩容20 min、输液或扩容40 min时心率(HR)、平均动脉压(MAP)、中心静脉压(CVP)、心脏指数(CI),外周血管阻力(SVR)的变化.监测H、G组患者扩容前后血细胞比容(Hct)的变化.结果 H、G组在扩容末,Hct下降,H组由术前0.385±0.043降至0.304±0.045,G组由术前0.395±0.035降至0.312±0.038.H、G组HR、MAP、CI、CVP、SVR术前值和麻醉诱导后值与C组的差异没有统计学意义(P>0.05).输液或扩容20 min、输液或扩容40 min时H、G组HR、CI、CVP、MAP高于C组,其差异有统计学意义(P<0.05);在扩容20 ml/kg后H组CVP增高达(13.13±3.51)cm H2O(1 cm H2O=0.098 kPa),G组增加达(14.88±1.33)cm H2O.结论 在40 min内静脉输入20 ml/kg的6%羟乙基淀粉、4%琥珀酰明胶,是一种有效的超容血液稀释方法.但会造成心脏负荷的显著增加,使用异氟醚和硝酸甘油能有效地减轻心脏前负倚.