Cross-Linking Reagents

交联试剂
  • 文章类型: Journal Article
    背景:有许多粘附屏障材料,交联或非交联透明质酸(HA),在手术中使用。
    目的:本研究探讨了交联和非交联HA预防跟腱粘连的疗效。我们假设非交联HA可能比交联HA更有效地预防跟腱损伤和修复后的粘连。
    方法:20只雄性SD大鼠,总共40条腿,接受跟腱横断和修复。手术后,用交联和非交联HA制剂同时治疗.将大鼠分为四组:阳性对照组,一组用BMC非交联HA凝胶治疗,一组用DEFEHERE交联HA凝胶治疗,和一组用ANIKA交联HA凝胶处理。手术四周后,对肌腱周围粘连进行了宏观评估和组织学分析,以评估治疗的有效性。
    结果:与交联HA和对照组相比,非交联BMCHA在预防肌腱粘连方面表现出优异的功效。组织学分析证实非交联HA组的粘连严重程度降低(P<0.05)。研究结果支持非交联HA作为抑制肌腱粘连的治疗方法的潜力。进一步研究,包括临床试验,有必要在人类受试者中验证这些结果。
    结论:非交联的BMCHA与交联的HA和对照组相比,在组织学分析中具有更低的肌腱粘连参数和更好的愈合评分。非交联HA有望作为抑制此类粘连形成的潜在治疗方法。
    BACKGROUND: There are many adhesion barrier materials, cross-linked or non-cross-linked hyaluronic acid (HA), used during surgeries.
    OBJECTIVE: This study investigates the efficacy of cross-linked and non-cross-linked HA in preventing Achilles tendon adhesions. We hypothesized that non-cross-linked HA may be more effective than cross-linked HA in preventing Achilles tendon adhesions following injury and repair.
    METHODS: Twenty male Sprague Dawley rats, totaling 40 legs, underwent Achilles tendon transection and repair. Following the surgery, they were treated simultaneously with cross-linked and non-cross-linked HA formulations. The rats were divided into four groups: a positive control group, a group treated with BMC non-cross-linked HA gel, a group treated with DEFEHERE cross-linked HA gel, and a group treated with ANIKA cross-linked HA gel. Four weeks after surgery, macroscopic evaluation of peritendinous adhesion and histological analysis were conducted to assess the effectiveness of the treatments.
    RESULTS: Non-cross-linked BMC HA demonstrated superior efficacy in preventing tendon adhesions compared to cross-linked HA and control groups. Histological analysis confirmed reduced adhesion severity in the non-cross-linked HA group (P < 0.05). The findings support the potential of non-cross-linked HA as a treatment to inhibit tendon adhesions. Further research, including clinical trials, is warranted to validate these results in human subjects.
    CONCLUSIONS: Non-cross-linked BMC HA had significantly lower tendon adhesions parameters and better healing scores in histological analysis than cross-linked HA and control group did. Non-cross-linked HA holds promise as a potential treatment to inhibit the formation of such adhesions.
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  • 文章类型: Journal Article
    对于蛋白质纤维,多元羧酸代表了在不使用甲醛的情况下增强耐久性的绿色策略。这项研究评估了用三种无甲醛交联剂:柠檬酸(CA),1,2,3,4-丁烷四羧酸(BTCA),和2-膦酰基丁烷-1,2,4-三羧酸(PBTCA)。结果表明,这些酸通过酯化和酰胺化与丝蛋白结合,提高洗涤耐久性。特别是,PBTCA将磷整合到丝绸中,提高阻燃性。虽然BTCA导致最高的体重增加和改善的皱纹恢复,它对丝织物的拉伸强度和柔软度产生了负面影响。相反,PBTCA巧妙地平衡了增强的抗皱性,对拉伸强度和柔软度的影响最小,并且对丝织物的白度影响最小,从而保持其美学吸引力。所有交联剂都提高了阻燃性,但是PBTCA表现出优越的性能,在80g/L浓度下实现32.4%的极限氧指数。在垂直燃烧试验中,经PBTCA处理的丝织物显示损伤长度减少,并表现出自熄性能,他们有资格为更高的阻燃等级。PBTCA中的磷促进燃烧过程中的焦炭形成,有效的阻燃和减少烟雾是必不可少的。这项研究强调了用PBTCA处理的丝绸的特殊潜力,展示其对要求苛刻的应用的适用性。
    For protein fibers, polycarboxylic acids represent a green strategy to enhance durability without using formaldehyde. This study evaluated the physical and flame retardant properties of silk fabrics treated with three formaldehyde-free crosslinkers: citric acid (CA), 1,2,3,4-butanetetracarboxylic acid (BTCA), and 2-phosphonobutane-1,2,4-tricarboxylic acid (PBTCA). Results showed that these acids bond with silk protein through esterification and amidation, improving washing durability. Particularly, PBTCA integrates phosphorus into silk, boosting flame retardancy. While BTCA led to the highest weight gain and improved wrinkle recovery, it negatively impacted the tensile strength and softness of silk fabrics. Conversely, PBTCA adeptly balanced enhanced wrinkle resistance with minimal effects on tensile strength and softness, and least affected the silk fabrics\' whiteness, thus preserving its aesthetic appeal. All crosslinkers improved flame retardancy, but PBTCA displayed superior performance, achieving a limiting oxygen index of 32.4 % at an 80 g/L concentration. In vertical burning tests, PBTCA treated silk fabrics showed reductions in damage length and demonstrated self-extinguishing properties, qualifying them for a higher flame retardant grade. Phosphorus in PBTCA promotes char formation during combustion, essential for effective flame retardation and smoke reduction. This research highlights the exceptional potential of silk treated with PBTCA, showcasing its suitability for demanding applications.
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  • 文章类型: Journal Article
    背景:我们旨在利用光学相干断层扫描血管造影(OCTA)来全面评估圆锥角膜患者角膜胶原交联(CCL)手术前后视神经头(ONH)和黄斑灌注的变化。
    方法:根据具体标准,共纳入了22名接受CCL手术的圆锥角膜患者,制定了细致的排除标准,以尽量减少潜在的混杂因素。参与者在CCL之前使用光谱OCT(海德堡)对ONH和黄斑进行了OCTA评估,以及在CCL后1个月和3个月。利用MATLAB软件进行图像分析。
    结果:参与者的平均年龄为20.09±6.11,其中59%为男性,术前平均眼压(IOP)为13.59±2.85mmHg。CCL后,乳头周围视网膜神经纤维层(ppRNFL)厚度和总体视网膜厚度保持稳定。然而,黄斑血管密度显著改变,强调血管反应的区域变化。对于黄斑大血管密度(LVD),浅血管复合体和深血管复合体(SVC和DVC)在术前和术后3个月随访之间均显示出显著差异(分别为p<0.001和p=0.002).视神经头标记物表现出相对稳定性,除了无血管复杂密度的变化,术前为49.2±2.2%,术后3个月降至47.6±1.7%(P值=0.005)。
    结论:虽然CCL似乎保持了某些眼部结构的完整性,CCL后黄斑灌注改变提示对视网膜供血的潜在影响.长期监测对于了解这些变化的影响至关重要,特别是在糖尿病等疾病的背景下。
    BACKGROUND: We aimed to employ Optical Coherence Tomography Angiography (OCTA) to comprehensively assess changes in the optic nerve head (ONH) and macular perfusion before and after the Corneal Collagen Cross-Linking (CCL) procedure in patients with keratoconus.
    METHODS: A total of 22 keratoconus patient\'s candidate for CCL procedures were included based on specific criteria, with meticulous exclusion criteria in place to minimize potential confounders. Participants underwent OCTA assessments of the ONH and macula using the Spectralis OCT (Heidelberg) before CCL, as well as at 1- and 3-months post-CCL. MATLAB software was utilized for image analysis.
    RESULTS: The mean age of the participants was 20.09 ± 6.11, including 59% male, and the mean intraocular pressure (IOP) before the surgery was 13.59 ± 2.85 mmHg. Peripapillary Retinal nerve fiber layer (ppRNFL) thickness and overall retinal thickness remained stable post-CCL. However, significant alterations were observed in macular vessel density, emphasizing regional variations in vascular response. For macular large vessel density (LVD), both superficial and deep vascular complex (SVC and DVC) demonstrated significant differences between before surgery and the 3 months post-surgery follow-up (p < 0.001 and p = 0.002, respectively). Optic nerve head markers demonstrated relative stability, except for changes in avascular complex density, which was 49.2 ± 2.2% before the surgery and decrease to 47.6 ± 1.7% three months after the operation (P-value = 0.005).
    CONCLUSIONS: While CCL appears to maintain the integrity of certain ocular structures, alterations in macular perfusion post-CCL suggest potential effects on retinal blood supply. Long-term monitoring is crucial to understand the implications of these changes, particularly in the context of conditions such as diabetes.
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  • 文章类型: Journal Article
    通常需要交联以改善胶原基支架的机械性能和稳定性。然而,将外源交联引入胶原中可能影响胶原结构。由于胶原蛋白的结构与其功能有关,重要的是研究交联的效果和选择保留胶原结构和机械性能的交联方法。这项研究比较了不同的物理(紫外线,UVC)和化学(京尼平,碳化二亚胺(EDC),和戊二醛)在接触拉伸的胶原复丝束上的交联方法,旨在概括肌腱的结构。对于所有交联方法,通过衰减全反射傅里叶变换红外光谱仪和广角X射线散射证实了胶原蛋白的存在和有序胶原蛋白结构的形成。胶原复丝束的形态在交联方法中是相似的。多丝束的溶胀在交联后急剧减少,并因交联方法而异。与Genipin和碳化二亚胺交联的标本溶胀最小。与非交联试样相比,所有交联试样的极限拉伸强度(UTS)和杨氏模量显著提高。戊二醛交联的胶原复丝束显示出最高的UTS值,范围为33.82±0.0MPa至45.528±0.757MPa。
    Crosslinking is usually required to improve the mechanical properties and stability of collagen-based scaffolds. Introducing exogenous crosslinks into collagen may however affect the collagen structure. Since the architecture of collagen is tied to its functionality, it is important to study the effect of crosslinking and to select a crosslinking method that preserves both the collagen structure and mechanical properties. The objective of this study is to compare the effect of various crosslinking methods on the structure and mechanical properties of bioartificial tendon-like materials (collagen multifilament bundles) fabricated by contact drawing. We examine both physical (ultraviolet light, UVC) and chemical (genipin, carbodiimide (EDC), and glutaraldehyde) crosslinking methods. The presence of collagen and the formation of well-ordered collagen structures are confirmed by attenuated total reflectance Fourier-transform infrared spectromicroscopy and wide-angle X-ray scattering for all crosslinking methods. The morphology of the collagen multifilament bundles is similar across crosslinking methods. Swelling of the multifilament bundles is dramatically reduced following crosslinking and varies by crosslinking method, with genipin- and carbodiimide-crosslinked specimens swelling the least. Ultimate tensile strength (UTS) and Young\'s modulus significantly improve for all crosslinked specimens compared to non-crosslinked specimens. Glutaraldehyde crosslinked collagen multifilament bundles display the highest UTS values ranging from 33.82±0.0 MPa to 45.59±0.76 MPa.
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  • 文章类型: Journal Article
    许多蛋白质自组装成二聚体和高阶寡聚体。因此,该方案的目标是表征感兴趣的内源性蛋白质的构象状态.这里,我们提出了一种使用化学交联评估细胞裂解物中蛋白质自组装的方案。我们描述了用重组蛋白进行化学交联的步骤,以及细胞培养和细胞裂解物制备的步骤。化学交联,SDS-PAGE,和蛋白质印迹检测内源性蛋白。有关此协议的使用和执行的完整详细信息,请参考Balaji等人1。
    Many proteins self-assemble into dimers and higher-order oligomers. Therefore, the goal of this protocol is to characterize the conformational states of an endogenous protein of interest. Here, we present a protocol for assessing protein self-assembly in cell lysates using chemical cross-linking. We describe steps for chemical cross-linking with recombinant proteins as well as steps for cell culture and cell lysate preparation, chemical cross-linking, SDS-PAGE, and western blotting for the detection of endogenous proteins. For complete details on the use and execution of this protocol, please refer to Balaji et al.1.
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  • 文章类型: Journal Article
    目的:比较在<400和>400微米的角膜厚度中使用低渗和等渗核黄素加速角膜胶原交联(CXL)后角膜生物力学和像差曲线的变化。分别。
    方法:这是一个前瞻性的,介入,比较研究涉及75例进行性圆锥角膜患者的100只眼。根据角膜厚度将眼睛分为两组:第1组包括角膜厚度<400微米且接受低渗性CXL的眼睛,第2组包括接受等渗CXL的角膜厚度>400微米的眼睛。评估并比较各组之间的角膜生物力学和像差特征。
    结果:在第1组中,除继发性散光外的所有高阶像差(HOA)均较基线显着降低;然而,在第2组中,仅昏迷和三叶下降。两组的角膜阻力因子和角膜滞后均有明显改善。2组明显高于1组。反向半径的变化,变形幅度,与第1组相比,第2组的断层生物力学指标显着改善。
    结论:低渗性CXL组的矫正视力改善和HOA降低明显更好;然而,等渗组角膜生物力学强度的改善明显更好。
    OBJECTIVE: To compare the changes encountered in corneal biomechanics and aberration profile following accelerated corneal collagen cross-linking (CXL) using hypo-osmolar and iso-osmolar riboflavin in corneal thicknesses of <400 and >400 microns, respectively.
    METHODS: This is a prospective, interventional, comparative study involving 100 eyes of 75 patients with progressive keratoconus. Eyes were divided into two groups based on corneal thickness: group 1 included eyes with a corneal thickness of <400 microns who underwent hypo-osmolar CXL, and group 2 included eyes with a corneal thickness of >400 microns who underwent iso-osmolar CXL. Corneal biomechanical and aberration profiles were evaluated and compared between groups.
    RESULTS: In group 1, all higher-order aberrations (HOA) except secondary astigmatism significantly decreased from baseline; however, in group 2, only coma and trefoil decreased. The corneal resistance factor and corneal hysteresis significantly improved in both groups, which was significantly greater in group 2 than in group 1. The change in inverse radius, deformation amplitude, and tomographic biomechanical index was significantly improved in group 2 as compared to group 1.
    CONCLUSIONS: Improvement in corrected distance visual acuity and decrease in HOA were significantly better in the hypo-osmolar CXL group; however, the improvement in biomechanical strength of the cornea was significantly better in the iso-osmolar group.
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  • 文章类型: Journal Article
    角膜胶原交联(CXL)是阻止圆锥角膜疾病进展的有效方法,导致锥形角膜的进行性角膜营养不良。尽管标准方案有效,该程序的相关步骤是进行上皮清创以促进核黄素药物的进入。核黄素,CXL协议中的一个关键分子,是角膜组织中的疏水性亲水性药物。本研究采用了细胞穿透肽(CPP),Tat2,以增强核黄素分子的渗透,从而改善了目前遵循的CXL协议。这项研究表明,CPP核黄素结合物的摄取增加了大约两倍,Tat2核黄素-5'磷酸盐(RiTe共轭物),在体外和体内。在本研究中,使用RiTe缀合物在兔角膜中引入并实施了两种不同的CXL方案(EppiON和EppiOFF)。标准和RiTe缀合物介导的CXL程序在两种方法中表现出相等程度的交联。在RiTe缀合物介导的CXL中减少的角膜细胞损失和无内皮损伤进一步确定了所提出的CXL方案的安全性。因此,RiTe缀合物介导的CXL方案作为标准圆锥角膜治疗的潜在替代方案,提供同样有效的,微创和患者依从性的治疗方式。
    Corneal collagen crosslinking (CXL) is an effective method to halt the disease progression of keratoconus, a progressive corneal dystrophy leading to cone shaped cornea. Despite the efficacy of standard protocol, the concerning step of this procedure is epithelial debridement performed to facilitate the entry of riboflavin drug. Riboflavin, a key molecule in CXL protocol, is a sparsely permeable hydrophilic drug in corneal tissues. The present study has employed cell penetrating peptide (CPP), Tat2, to enhance the penetration of riboflavin molecule, and thereby improve currently followed CXL protocol. This study demonstrates approximately two-fold enhanced uptake of CPP riboflavin conjugate, Tat2riboflavin-5\'Phosphate (RiTe conjugate), both in vitro and in vivo. Two different CXL protocols (Epi ON and Epi OFF) have been introduced and implemented in rabbit corneas using RiTe conjugate in the present study. The standard and RiTe conjugate mediated CXL procedures exhibited an equivalent extent of crosslinking in both the methods. Reduced keratocyte loss and no endothelial damage in RiTe conjugate mediated CXL further ascertains the safety of the proposed CXL protocols. Therefore, RiTe conjugate mediated CXL protocols present as potential alternatives to the standard keratoconus treatment in providing equally effective, less invasive and patient compliant treatment modality.
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  • 文章类型: Journal Article
    该研究涉及使用5%-20%范围内的不同量的柠檬酸(CA)制备和表征交联羧甲基纤维素(CMC)膜。w/w,相对于CMC的干重。通过傅里叶变换红外光谱等技术,X射线光电子能谱,羰基含量分析,和凝胶分数测量,确认CMC和CA之间的成功交联。调查包括化学结构分析,物理和光学特性,溶胀行为,水蒸气透过率,水分含量,和表面形态。当与非交联CMC膜相比时,交联CMC膜的耐水性表现出显著的改善。研究结果表明,用10%CA交联的膜表现出作为可食用涂层应用的有利性质。这些透明膜,理想的包装,证明有效保存新鲜香蕉的质量和感官属性,包括颜色保持,最小化的重量损失,通过抑制淀粉体降解减缓成熟,并增强了储存期间的坚固性。
    The study involves the preparation and characterization of crosslinked-carboxymethyl cellulose (CMC) films using varying amounts of citric acid (CA) within the range 5 %-20 %, w/w, relative to the dry weight of CMC. Through techniques such as Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, carbonyl content analysis, and gel fraction measurements, the successful crosslinking between CMC and CA is confirmed. The investigation includes an analysis of chemical structure, physical and optical characteristics, swelling behavior, water vapor transmission rate, moisture content, and surface morphologies. The water resistance of the cross-linked CMC films exhibited a significant improvement when compared to the non-crosslinked CMC film. The findings indicated that films crosslinked with 10 % CA demonstrated favorable properties for application as edible coatings. These transparent films, ideal for packaging, prove effective in preserving the quality and sensory attributes of fresh bananas, including color retention, minimized weight loss, slowed ripening through inhibiting amyloplast degradation, and enhanced firmness during storage.
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  • 文章类型: Journal Article
    目的:为了比较视觉,屈光,在儿童和成人进行性圆锥角膜(KC)患者之间进行了12个月的随访后,高辐照度加速角膜交联(ACXL)方案的地形结果。
    方法:回顾性,比较,队列研究。KC患者分为两组:儿科(≤18岁)和成人(>18岁)。所有这些都用epi-OFFACXL(30mW/cm2,8分钟,脉冲1:1开和关=7.2J/cm2)。视觉,屈光,术前和术后1,3,6和12个月测量地形图值.KC进展,定义为随访期间Kmax增加≥1D,被记录下来。
    结果:89只眼(53例)纳入分析;45只(50.6%)眼来自儿科患者,44只(49.4%)眼来自成人。在一年的随访中,儿科患者的进展率显着较高(22.2%vs.4.5%,p=.014)。相反,女性(Beta=-3.62,p=0.018),Snellen的基线未矫正视力≥20/60(Beta=-5.96,p=.007),ACXL治疗≥15年(β=-0.31,p=.021)与非进行性疾病相关。最佳矫正视力的显著改善,Kmin,Km,记录两组的Kmax。总的来说,两组均有86.5%的眼显示Kmax稳定或改善。
    结论:尽管视觉上相似,屈光,两组的地形结果,在随访1年时,年龄较小与ACXL后KC进展相关.
    OBJECTIVE: To compare the visual, refractive, and topographic outcomes of a high irradiance accelerated corneal crosslinking (ACXL) protocol after a 12-month follow-up between pediatric and adult patients with progressive keratoconus (KC).
    METHODS: Retrospective, comparative, cohort study. Patients with KC were divided into two groups: pediatric (≤ 18 years) and adult (> 18 years). All of them were managed with epi-OFF ACXL (30 mW/cm2, 8 min, pulsed 1:1 on and off = 7.2 J/cm2). Visual, refractive, and topographic values were measured preoperatively and at 1, 3, 6, and 12 months postoperative. KC progression, defined as a Kmax increase of  ≥ 1D during follow-up, was recorded.
    RESULTS: Eighty-nine eyes (53 patients) were included for analysis; 45 (50.6%) eyes were from pediatric patients and 44 (49.4%) from adults. At one-year follow-up, pediatric patients experienced significantly higher rates of progression (22.2% vs. 4.5%, p = .014). Contrariwise, female gender (Beta = - 3.62, p = .018), a baseline uncorrected visual acuity of Snellen ≥ 20/60 (Beta = - 5.96, p = .007), and being ≥ 15 years at ACXL treatment (Beta = - 0.31, p = .021) were associated with non-progressive disease. A significant improvement in best-corrected visual acuity, Kmin, Km, and Kmax was recorded in both groups. Overall, 86.5% of eyes from both groups showed Kmax stabilization or improvement.
    CONCLUSIONS: Despite the similarity in visual, refractive, and topographic outcomes in both groups, younger age was associated with KC progression after ACXL at one year of follow-up.
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  • 文章类型: Journal Article
    目的:比较高氧下定制的经上皮(epi-on)角膜交联(CXL)和室内空气下定制的CXL上皮去除(epi-off)治疗圆锥角膜(KC)的临床结果。
    方法:于默奥大学医院,于默奥,瑞典。
    方法:前瞻性,随机化,单面具,个体内比较研究。
    方法:32例双侧进行性KC患者接受双侧定制地形图引导CXL治疗,30mW/cm2;7.2-15J/cm2,并随机分为一只眼睛(32只眼睛)和另一只眼睛(32只眼睛)。未矫正(UDVA)和最佳矫正视力(BCVA),最大角膜曲率(Kmax),主观眼部不适,低对比度视力(LCVA)在10%和2.5%的对比度,眼和前角膜波前像差,明显折射等效球面(MRSE),在24个月内评估内皮细胞计数(ECC)和不良事件.
    结果:两种治疗在24个月时都显示出UDVA的改善;-0.16±0.24(p<0.001)和-0.13±0.20logMAR(p=0.006),分别,BCVA;-0.10±0.11(p<0.001)和-0.10±0.12(p=0.001),Kmax;-1.74±1.31(p<0.001)和-1.72±1.36D(p<0.001)。两种方案的LCVA都提高了10%(p<0.001),但仅epi-onCXL的LCVA提高了2.5%(p=0.001)。ECC没有改变,没有不良事件发生。在整个治疗后的第一周内,epi-on眼睛的不适症状明显减少(p<0.05)。
    结论:高氧定制epi-onCXL是室内空气定制epi-offCXL的可行替代方案,BCVA和LCVA的改善更快,早期眼部不适更少。
    OBJECTIVE: To compare clinical outcomes of customized transepithelial (epi-on) corneal crosslinking (CXL) in high oxygen and customized CXL with epithelial removal (epi-off) in room air for keratoconus (KC).
    METHODS: Umeå University Hospital, Umeå, Sweden.
    METHODS: Prospective, randomized, single-masked, intraindividually comparing study.
    METHODS: 32 participants with bilateral progressive KC were treated with bilateral customized topography-guided CXL, 30 mW/cm 2 ; 7.2 to 15 J/cm 2 and were randomized to epi-on in one eye (32 eyes) and epi-off in the fellow eye (32 eyes). Uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA), maximal keratometry (Kmax), subjective ocular discomfort, low-contrast visual acuities (LCVAs) at 10% and 2.5% contrast, ocular and anterior corneal wavefront aberrations, manifest refractive spherical equivalent, endothelial cell count (ECC), and adverse events were assessed through 24 months.
    RESULTS: Both treatments showed improvements at 24 months in UDVA; -0.16 ± 0.24 ( P < .001) and -0.13 ± 0.20 logMAR ( P = .006), respectively, CDVA; -0.10 ± 0.11 ( P < .001) and -0.10 ± 0.12 ( P = .001), Kmax; -1.74 ± 1.31 ( P < .001) and -1.72 ± 1.36 D ( P < .001). LCVA 10% improved for both protocols ( P < .001), but LCVA 2.5% improved for epi-on CXL only ( P = .001). ECC was unaltered, and no adverse events occurred. The epi-on eyes had significantly less discomfort symptoms during the whole first week posttreatment ( P < .05).
    CONCLUSIONS: High-oxygen customized epi-on CXL is a viable alternative to room air customized epi-off CXL, with faster improvements in CDVA and LCVA and less early ocular discomfort.
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