CN115666665A - 拉绒涂覆的伤口敷料 - Google Patents
拉绒涂覆的伤口敷料 Download PDFInfo
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- CN115666665A CN115666665A CN202180041282.8A CN202180041282A CN115666665A CN 115666665 A CN115666665 A CN 115666665A CN 202180041282 A CN202180041282 A CN 202180041282A CN 115666665 A CN115666665 A CN 115666665A
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- wound dressing
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Abstract
本发明涉及一种可吸收止血贴片,该可吸收止血贴片利用一种生物相容性纤维织物基材,该生物相容性纤维织物基材是熔喷的并且在表面处是拉绒或松散的,并且该基材具有低轮廓、高柔韧性、强度和孔隙率,该孔隙率适于涂覆可交联活性分子并最终有效用作有问题出血情况中的止血剂。
Description
背景技术
包含两种可交联组分的可吸收止血贴片已在文献中描述,包括在美国公开2011/0045047A1中。用于此类贴片的可交联组分可以是一对共反应性化合物或涂覆有共反应性化合物的基材,该共反应性化合物具有可与基材上的对应共反应性基团形成共价交联的可用单元。引发、增强和/或支持生成纤维蛋白凝块的止血级联的血浆衍生的生物组分也已经应用于各种构造和材料的基材上。
发明内容
本发明涉及一种用于密封的可吸收止血贴片,更具体地,涉及一种经济上可行的弹性分层非织造基质基材,该弹性分层非织造基质基材由在表面处拉绒或疏松的熔喷微纤维组成,以获得高的组织粘附。在高度功能性低轮廓止血贴片的开发中,拉绒基材独特地具有高表面积和用于涂覆可交联活性分子(例如PEG)的适合性,否则将缺乏良好的组织粘附特性。
本发明涉及一种可吸收止血非织造贴片和伤口敷料,该伤口敷料利用在表面处熔喷和拉绒或疏松的生物相容性纤维织物基材;并且该基材具有低轮廓、高柔韧性、强度和孔隙率,该孔隙率适于涂覆可交联活性分子并最终有效用作有问题出血情况中的止血剂。
附图说明
图1是单独的熔喷贴片的示意性分解图,其表面纤维升高,并且通过拉绒方法增加基质蓬松度。
图2示出了非拉绒和不同拉绒程度作为基材的横截面图像的比较。
图3示出了同样涂覆的非拉绒(顶部)和拉绒(底部)基材的悬空(左)和横截面(右)SEM图像。
图4示出了经由显微CT得到的同样涂覆的非拉绒(顶部)和拉绒(底部)基材的图像。
具体实施方式
本发明涉及特别适于涂覆的基质,因为拉绒表面具有增加的表面积,以用于涂覆非织造基质中的单独熔喷纤维。优选的高基质蓬松度是经由拉绒的方法生产的,该方法疏松紧密缠结的纤维,增加基质蓬松度和总体体积,这使得随后施加的涂层具有更大的渗透深度。
本发明的益处之一是所得的伤口敷料具有多侧面,因为已经拉绒的表面可以容易地被识别为应当施用到组织表面上的拉绒的和涂覆的面。
本发明的伤口敷料表现出对组织的强贴片粘附,因为拉绒表面导致更高量的涂覆纤维和更大的表面粗糙度两者,它们一起增强了贴片-组织界面处的粘附。
本发明的另一个优势是易于处理的低轮廓贴片,具有当拉绒时不损害功能性的相对低的厚度和密度,并且可以在更小的空间中容易地处理。贴片还可能需要降低的密封压缩时间。
本发明的另一个优势是可以调节拉绒的程度以允许特定的特征,例如随着增加拉绒的程度而降低刚度。
本发明的伤口敷料表现出高组织适形能力,因为如果组织膨胀或移动,弹性分层和粗糙化基质的组合允许与组织的高顺应性。
在一个实施方案中,本发明可被生产为具有定制的吸收时间/生物相容性,因为熔喷非织造基质可使用生物相容性且可吸收的材料通过例如分别在熔融挤出和结晶期间预照射和/或调节纤维直径和聚合物结构来制造。
在一个实施方案中,非织造基础基材由可吸收且生物相容的聚酯材料诸如乙交酯和ε-己内酯的共聚物通过含有几百个小孔的线性模具挤出而生成。会聚的热空气流使熔融聚合物变细以形成直径极细的纤维。高速空气将纤维吹到收集圆筒上,形成一片熔喷非织造织物。选择工艺因素,诸如圆筒速度和圆筒与模具表面之间的距离,以在成形幅材上获得优选的纤维直径和取向,其反过来控制所得非织造基质的纤维直径、孔径和密度。
虽然圆筒尺寸取决于聚合物挤出模具的长度,但它是任意的,并且可以按比例增加用于大规模制造熔喷片材。圆筒速度与每单位面积的非织造基质密度成反比,并且固有地与纤维直径、比表面积和层中的总体孔隙率相关联。当增加聚合物挤出模具和圆筒之间的间隙时,收集器距离也影响基质特征,从而更好地使纤维厚度和取向随机化。
本发明确定的优选的圆筒速度在0.08m/s-0.41m/s的范围内,更优选0.12m/s-0.37m/s,最优选0.15m/s-0.2m/s,并且距离在10英寸-40英寸的范围内,更优选在15-35的范围内,最优选在20-30的范围内,以便定制和生成微孔、不透水和低轮廓(厚度)的非织造膜。
这些范围是使用建立的,其材料特性(例如,1.67的特性粘度)可能会在小程度上影响纤维特征,进而影响整个基质的孔隙率、密度和刚度。然而,无论材料特性如何,这些范围应显示相同的趋势(例如,对于和((Polyglactin 910、聚乙醇酸)两者,增加圆筒速度将降低贴片密度,并且至少我们确定的范围是可行的起点)。可熔喷的感兴趣的可生物降解聚合物包括但不限于聚乙醇酸(PGA)、聚(乳酸-共-乙醇酸)(PLGA)、聚乳酸(PLA)、聚对二氧环己酮(PDS)和己内酯/乙交酯聚酯,诸如聚(己内酯-共-乙交酯)。
本发明在拉绒之前确定的优选的厚度范围为0.30mm-1.5mm,更优选0.6mm-0.95mm,最优选0.85mm-90mm。虽然该起始厚度可以变化,但拉绒后,本发明确定基质高度的优选增加范围为原始厚度的大约50%-250%,更优选55%-175%,最优选125%-165%。
本发明确定的优选密度在140mg/cm3-250mg/cm3,更优选140mg/cm3-200mg/cm3,最优选140mg/cm3-150mg/cm3的范围内。预期密度在拉绒后不显著改变。
基于显微CT分析,本发明确定优选的孔径分布在0.01mm-0.5mm的范围内,大多数孔在0.1mm-0.3mm的范围内。另外,根据显微CT分析,本发明确定基质的总开口孔隙率为大约85%。
熔喷这些聚合物在生成超细纤维方面提供了独特的优势。本发明的熔喷非织造物确定了细纤维,并且纤维的直径在1微米-250微米的范围内,优选在1微米-90微米的范围内。
在一个实施方案中,在拉绒之前,通过在前者片材结晶之前将另一片熔喷聚酯基非织造物挤出到收集圆筒上而生成独立的熔喷贴片。将多个离散的片材沉积到圆筒上以产生多层基质。然后,通过拉绒将表面改性以增加用于涂层和多侧面的表面积。拉绒效果通过使用研磨技术以机械地升高贴片表面上的纤维端部并且同时还随着表面下的纤维缠结从该过程中被疏松而增加基质蓬松度来实现。
目前的拉绒方法采用手动工具和自动工具两者。对于手动拉绒,使用钢档案卡(例如3.75")单向地刷非织造织物的表面若干次,直到纤维开始从表面脱落(对于该方法,5次-15次是优选的工作范围)。对于自动拉绒,使用具有卷曲钢丝轮(例如0.25"杆,3"直径)附件的台式钻床。也可利用其它器械诸如玻璃、钢丝刷和研磨片轮来实现不同程度的拉绒。另外,也可以利用高压空气、真空或水射流来疏松基质。为了在没有破坏性磨损的情况下实现广泛拉绒,可以在刷之前使基质经受加热以软化纤维。拉绒增加了用于涂覆可交联活性分子的横截面积和比表面积(图1),这最终提供了止血贴片与组织的优异的结构整合的潜力以增强粘附。
拉绒的程度可通过测量由该方法产生的增加的横截面高度和每密度的面积来表征。中度拉绒表面的最优选方法升高平均纤维以提供161%的基质高度增加(图2;表1)。
表1.从拉绒开始增加的基质高度
条件 | 密度(mg/cm<sup>2</sup>) | 基质高度Δ(%) |
基材A;无拉绒 | 13.6 | - |
基材A;轻度拉绒 | 13.2 | 54.70 |
基材B;无拉绒 | 13.3 | - |
基材B;中度拉绒 | 13.3 | 161.11 |
基材C;无拉绒 | 12.9 | - |
基材C;高度拉绒 | 12.8 | 252.81 |
中度拉绒表面的最优选方法使横截面积增加152%(图2,表2)。在所有情况下,密度变化是最小的。
表2.
条件 | 非拉绒面积(px<sup>2</sup>) | 拉绒后面积(px<sup>2</sup>) | 基质面积Δ(%) |
基材A,轻度拉绒 | 26.17 | 41.15 | 57.24 |
基材B,中度拉绒 | 26.91 | 67.88 | 152.25 |
基材C,高度拉绒 | 24.31 | 129.86 | 434.18 |
优选基材的定量分析表明,中度拉绒分别使基质高度、表面粗糙度和体积增加642%、672%和8999%(表3)。
表3.
拉绒 | 最大高度(um) | 表面粗糙度Sa(um) | 体积(μm^3) |
无 | 1006 | 108 | 4.4E09 |
轻度 | 4635 | 759 | 2.7E11 |
中度 | 7503 | 835 | 4.0E11 |
高 | 10465 | 1405 | 5.5E11 |
无VS轻度(%Δ) | 361 | 602 | 5992 |
无VS中度(%Δ) | 646 | 672 | 8999 |
无VS高度(%Δ) | 940 | 1198 | 12465 |
涂覆没有拉绒的基质导致材料渗透性差和聚集或结块,而拉绒显示出改善的单独纤维的涂覆和向基质中更好的渗透。横截面SEM显微术显示出拉绒减轻了“平膜”的问题,其中涂层在表面处结块,阻塞了多孔结构的益处并且增加了刚度(图3)。
另外,在非拉绒涂层中观察到更多的裂纹。图像分析证实,非拉绒组仅具有少量孔并且表面处的空隙空间占总表面积的12%,而拉绒组具有27%的面积。
单独纤维的涂覆和拉绒基材中更少的结块显示出改善的孔体积和空隙空间(15%),这将有利于血液渗透和增强涂覆纤维对组织的联锁。为了进一步证实这些基质特征,进行显微CT成像以了解拉绒表面上的涂层。所述可视化不仅再次确认拉绒如何改善基质蓬松度,而且导致改善的涂层渗透和增加的表面处孔隙率。横截面分析显示拉绒破坏了在非拉绒条件下看到的均匀膜状涂层,并且有效地分散了交联剂而不阻塞基质基材的微孔结构(图4)。最后,孔隙率提高,并且刚度分别降低13.8%和50%(表4)。
表4.
样品名称 | 总孔隙率(%) | 平均刚度(N/mm) |
非拉绒,涂覆 | 41.4 | 0.02 |
拉绒,涂覆 | 55.2 | 0.01 |
功能评估使用组织剥离测试和肝素化脾体外出血模型来执行。对于合格的剥离测试,将贴片施加到小腿皮组织并在剥离前在Tris缓冲盐水中压缩,并且在90°下测量力。
对于止血功效的体外评估,拉绒的、涂覆的、非拉绒涂覆的和非拉绒的、未涂覆的各自作为非织造基材来评价出血减少。简言之,将每个贴片切割成1"×1"正方形,放置在体外脾模型(用肝素化牛血灌注)中的10mm圆形活检缺陷上,填塞2分钟。定量分析证实体外模型中的出血通过使用涂覆的拉绒熔喷贴片而被最小化或完全阻止。
这些数据证实,除了改善的组织粘附之外,止血贴片是完全功能性和有效的。不同程度的拉绒影响了止血剂的有效性。虽然所有的贴剂确实减少了出血并最终密封以阻止,但是如前所述的轻度或高度拉绒与中度拉绒相比具有降低的有效性。
在一个实施方案中,由拉绒熔喷基质基材与可交联涂层的组合构成的高粘附性止血贴片可使用可吸收且生物相容的聚酯材料(诸如),以0.17m/s(优选地在0.09m/s至0.34m/s的测试范围内)的圆筒速度和25英寸(优选地在12英寸至25英寸的范围内)的收集器距离,由熔喷微纤维幅材制备。可以在收集器圆筒上直接构建四层,并且优选2层-10层的范围。当使用等于1.6的IV时,四层构造的所得密度为大约13mg/cm2。在拉绒之前需要这些材料特征和密度。
优选的拉绒程度通过研磨技术实现,所述研磨技术疏松纤维缠结,将表面纤维和总体基质高度升高大约161%,并且优选55%-253%的范围,同时横截面积随后增加大约152%,并且优选57%-434%的范围。所得基材可具有分别大约676%和8999%的增加的表面粗糙度和体积。
拉绒方法包括手动工具和自动工具两者。手动拉绒可通过但不限于钢丝刷、钢档案卡、玻璃或具有可用于产生磨损的粗糙边缘的类似工具/材料来实现。为了实现优选的拉绒程度,使用钢档案卡(3.75")单向地刷非织造织物的表面若干次,直到纤维开始从表面上撕掉(对于该方法,5-15次是优选的工作范围,其中5次导致“轻度”拉绒,并且15次导致“高度拉绒”)。另选地,自动拉绒方法包括但不限于与卷曲钢丝轮(例如0.25"杆,3"直径)或其它基于刷的附件一起使用的台式钻床。也可以利用其它动力器械和附件,诸如钢丝刷和研磨片轮,以实现不同程度的拉绒。
可交联活性物质,诸如聚乙二醇活性酯(例如,PEG-琥珀酰亚胺戊二酸酯),优选在有或没有缓冲剂和添加剂的情况下依次涂覆,以形成全功能性止血剂。为了减少实践的想法,将拉绒后的2英寸乘4英寸熔喷基质用深嵌入多孔基材中的浅层缓冲液超声喷涂(溶解方法)或浸涂(不溶解方法):工作示例包括1.25mg/cm2的硼酸钠,或2mg/cm2 Bis-Tris或1mg/cm2的碳酸氢钠。然后,超声涂覆15mg/cm2的4臂-PEG-胺-HCl(分子量:10Kda),再超声涂覆18mg/cm2的4臂-PEG-SG(分子量:10Kda)。拉绒构造允许可交联活性物质的独特沉积,这导致增强的组织粘附。
示例性的血浆衍生的(或相关的)止血剂包括蛋白质和肽,并且因此不限于天然的止血剂,并且可以是重组的或合成的形式;具有止血活性的凝血酶原、凝血酶、纤维蛋白、纤连蛋白、因子(Factor)X/Xa、因子VII/VIIa、因子IX/IXa、因子XI/XIa、因子XII/XIIa、组织因子、血管性血友病因子、弹性蛋白、白蛋白、血小板表面糖蛋白、血管加压素和由类似物组成的血管加压素组、肾上腺素、选择素、纤溶酶原激活物抑制剂、血小板激活剂、合成肽以及它们的任何组合。
载体子层可以是非织造材料的形式。示例性的构造材料是合成聚合物。基材可以由选自脂族聚酯聚合物和/或一种或多种单体的共聚物的组分组成,该单体选自D-乳酸、L-乳酸、丙交酯(包括L-、D-、内消旋形式)、乙醇酸、乙交酯、己内酯、对二氧环己酮和三亚甲基碳酸酯以及它们的混合物或共混物。
基材可另选地或附加地由脂族聚酯聚合物、共聚物或它们的共混物的织物层组成。脂族聚酯通常在单体的开环聚合中合成,该单体包括但不限于丙交酯(包括L-和D-、内消旋形式)、乙醇酸、乙交酯、己内酯、对二氧环己酮(1,4-二恶烷-2-酮)和三亚甲基碳酸酯(1,3-二恶烷-2-酮)。在一些情况下,脂族聚酯可通过例如D-乳酸、L-乳酸和/或乙醇酸的缩聚制备。在一种形式中,织物包含乙交酯和丙交酯的共聚物,其量为乙交酯和剩余丙交酯的约70摩尔%至95摩尔%。
敷料的多孔基材在其表面的至少一部分上具有开口或孔。如下文更详细的描述,用于形成多孔基材的合适材料包括但不限于纤维结构。在实施方案中,孔可具有足够的数量和尺寸以便在多孔基材的整个厚度上互连。
多孔基材的一个或多个子层可为至少0.1cm厚,在某些实施方案中为约0.2cm至约1.5cm厚。多孔基材的子层中的孔的尺寸可为约2微米至约300微米,在实施方案中为约50微米至约150微米。可以想象,基材的子层的孔可以以任何方式布置在基材中。例如,孔可以以随机或均匀的方式构造。在一些实施方案中,可使用海藻酸钙或海藻酸铜形成孔以产生蜂巢形状的多孔基材。在其它实施方案中,孔可被构造成在多孔基材中产生梯度。该梯度可进一步增强多孔基材吸收生理流体并引导携带第一共反应性组分的生理流体向第二共反应性组分迁移的能力。
在一个实施方案中,基材具有施用到第一子层上的第一共反应性组分和施用到其上的第二共反应性组分。术语“第一共反应性组分”和“第二共反应性组分”各自是指聚合物、官能聚合物、大分子、小分子或交联剂,它们可参与反应以形成交联分子网络,例如水凝胶。
在一个实施方案中,第一共反应性组分和第二共反应性组分各自是多官能的,是指其包含两个或更多个亲电子或亲核官能团,使得例如第一共反应性组分上的亲核官能团可与第二共反应性组分上的亲电子官能团反应以形成共价键。第一共反应性组分或第二共反应性组分中的至少一者包括两个以上官能团,使得由于亲电子-亲核反应,前体结合形成交联聚合物产物。此类反应被称为“交联反应”。
在某些实施方案中,第一共反应性组分和第二共反应性组分各自仅包含一类官能团,或者仅包含亲核基团或者仅包括亲电子官能团,只要在交联反应中同时使用亲核前体和亲电子前体。因此,例如,如果第一共反应性组分具有亲核官能团诸如胺,则第二共反应性组分可具有亲电子官能团诸如N-羟基琥珀酰亚胺。另一方面,如果第一共反应性组分具有亲电子官能团诸如磺基琥珀酰亚胺,则第二共反应性组分可具有亲核官能团诸如胺或硫醇。因此,可以使用官能聚合物,例如蛋白质、聚(烯丙基胺)、苯乙烯磺酸或胺封端的二官能或多官能聚(乙二醇)(“PEG”)。
第一共反应性组分和第二共反应性组分可具有生物惰性和水溶性核。当核是水溶性的聚合物区域时,可以使用的优选聚合物包括:聚醚,例如,聚环氧烷诸如聚乙二醇(“PEG”)、聚环氧乙烷(“PEO”)、聚环氧乙烷-聚环氧丙烷共聚物(“PPO”)、聚环氧乙烷嵌段共聚物或无规共聚物和聚乙烯醇(“PVA”);聚(乙烯吡咯烷酮)(“PVP”);聚(氨基酸);多糖,诸如葡聚糖、壳聚糖、藻酸盐、羧甲基纤维素、氧化纤维素、羟乙基纤维素、羟乙基纤维素、透明质酸;以及蛋白质,诸如白蛋白、胶原、酪蛋白和明胶。聚醚以及更特别是聚(氧化烯)或聚(乙二醇)或聚乙二醇特别有用。当核本质上是小分子时,各种亲水官能团中的任何一种都可用于使第一共反应性组分和第二共反应性组分成为水溶性的。例如,水溶性的官能团如羟基、胺、磺酸酯和羧酸酯可用于制备水溶性前体。此外,辛二酸的N-羟基琥珀酰亚胺(“NHS”)酯不溶于水,但通过向琥珀酰亚胺环添加磺酸酯基团,可使辛二酸的NHS酯成为水溶性的,而不影响其对胺基的反应性。
在某些实施方案中,第一共反应性组分和第二共反应性组分都可以是能够交联的大分子。例如,在实施方案中,前体之一可以是分子量为约2,000至约20,000道尔顿的多官能PEG。在具有亲电子基团的实施方案中,该多官能PEG可与分子量为约100,000道尔顿的胶原反应。在其它实施方案中,可使用分子量为约50,000至约100,000道尔顿的明胶代替胶原。
在另一个实施方案中,在贴片上提供共反应性组分和缓冲剂。示例性的密封贴片/垫片包括:PEG-NH2*HCl和PEG-NHS,即缓冲盐试剂,其优选作为碱性缓冲剂(硼砂)沉积在可吸收基材上。
如果期望由第一共反应性组分和第二共反应性组分的反应产生的生物相容性交联聚合物是可生物降解的或可吸收的,则第一共反应性组分和第二共反应性组分中的一者或多者可具有存在于官能团之间的可生物降解的连接键。可生物降解的连接键还可以可选地用作前体中的一个或多个前体的水溶性核。在替代方案中,或此外,可以选择第一共反应性组分和第二共反应性组分的官能团,使得它们之间的反应产物产生可生物降解键。对于每种方法,可选择可生物降解键,使得所得可生物降解的生物相容性交联聚合物将在期望的时间段内降解、溶解或吸收。优选地,选择在生理条件下降解成无毒产物的可生物降解键。
可生物降解的连接键可以是螯合物或化学或酶促可水解或可吸收的。示例性的化学可水解的可生物降解键包括乙交酯、d-丙交酯、丙交酯、己内酯、二氧环己酮和三亚甲基碳酸酯的聚合物、共聚物和低聚物。示例性的酶可水解的可生物降解键包括可被金属蛋白酶和胶原酶裂解的肽键。其它示例性的可生物降解键包括聚(羟基酸)、聚(原碳酸酯)、聚(酸酐)、聚(内酯)、聚(氨基酸)、聚(碳酸酯)、聚(糖)和聚(膦酸酯)的聚合物和共聚物。在实施方案中,可生物降解键可以含有酯键。一些非限制性示例包括琥珀酸、戊二酸、丙酸、己二酸或氨基酸的酯以及羧甲基酯。
在实施方案中,多官能亲电子聚合物诸如用多个NHS基团官能化的多臂PEG可用作第一共反应性组分,并且多官能亲核组分诸如三赖氨酸可用作第二共反应性组分。在其它实施方案中,多官能亲电子聚合物诸如用多个NHS基团官能化的多目标PEG可用作第一共反应性组分,并且多官能亲核聚合物诸如胶原和/或胶原衍生物可用作第二共反应性组分。用多个NHS基团官能化的多臂PEG可以例如具有四个、六个或八个臂并且具有约5,000至约25,000的分子量。适合的第一前体和第二前体的许多其它示例描述于美国专利6,152,943、6,165,201、6,179,862、6,514,534、6,566,406、6,605,294、6,673,093、6,703,047、6,818,018、7,009,034和7,347,850中,其各自的全部内容通过引用并入本文。
对于贴片实施方案,共反应性组分可以作为单独层沉积在基质上。另选地,共反应性组分可以作为混合物沉积。层的排序可以改变,但优选的密封贴片或垫片的顺序包括PEG-NH2*HCl(或任何其它氢卤化物)、PEG-NHS和缓冲盐(例如四硼酸钠、MES、TRIS、双(2-羟乙基)氨基(三羟甲基)甲烷(Bis-Tris)、碳酸氢钠)与基质,然后是缓冲盐层、受保护的PEG-胺层和PEG-NHS层。此外,臂的数量和材料的分子量可以改变,但是从功效和稳定性的观点来看,4臂-10K-NH2*HCl和4臂-10K-NHS是优选的变体。该实施方案以不同的涂层顺序进行了评估。使用喷涂工艺沉积的缓冲剂在基质上的位置极大地影响性能和稳定性。当缓冲剂沉积在两种PEG下方(即,当施用基质时离组织最远)时,性能和稳定性最佳。
可使用本领域技术人员已知的任何合适的方法将第一共反应性组分施用到多孔基材上,这些方法包括但不限于喷涂、刷涂、浸渍、浇注、层压等。在实施方案中,第一共反应性组分可以能够形成止血敷料的任何浓度、尺寸和构型作为涂层施用到基材上。在实施方案中,第一共反应性组分涂层可穿透多孔基材的孔。在实施方案中,第一共反应性组分可以作为层压到基材的至少一侧上的膜施用到多孔基材上。
同样可使用本领域技术人员已知的任何合适的方法将第二共反应性组分施用到多孔基材上,这些方法包括但不限于喷涂、刷涂、浸渍、浇注、层压等。在其它实施方案中,可以将第二共反应性组分以溶液形式施用到多孔基材上,然后蒸发或冻干溶剂。在实施方案中,第二共反应性组分可以作为在基材的至少一侧上的涂层或作为层压到基材的至少一侧上的膜施用到多孔基材上。
在使用期间,贴片敷料被定向为将共反应性组分直接施用到组织上。在实施方案中,第一部分和第二部分可通过添加对比染料、表面纹饰、着色或其它视觉提示而彼此区分。在与组织诸如受伤组织接触时,敷料将吸收生理流体,并且第一共反应性水凝胶组分将被流体溶解。当液体渗入并通过敷料迁移时,流体将携带溶解的第一共反应性组分进入第二共反应性组分和缓冲剂。最终,第一共反应性组分和第二共反应性组分将反应形成生物相容性交联材料,从而在支架降解时帮助凝块稳定化、组织向内生长和重塑。在一些实施方案中,通过第一共反应性组分和第二共反应性组分的反应产生的生物相容性交联材料还为敷料提供抗粘附特性。
以下实施例仅提供用于说明目的,并不旨在限制本公开的范围。
基质和拉绒方法示例:
使用可吸收且生物相容的聚酯材料诸如将熔喷微纤维幅材挤出到圆筒上,其中最优选的圆筒速度为0.17m/s,并且圆筒距模头的距离为25英寸。当使用等于1.6的IV时,在收集器圆筒上直接构建四层这种构造,所得密度为大约13mg/cm2。在拉绒之前需要这些材料特征和密度。
在切割成2英寸乘4英寸熔喷基质后,将非织造贴片温和地加热至50℃持续15分钟以软化纤维,并且然后通过使用4"钢档案卡(steel file card)单向地刷表面来拉绒,直到总体基质高度增加大约150%。
涂覆方法实施例:
超声喷涂(溶解法)或浸涂(不溶物法)2英寸×4英寸的熔喷拉绒基质,用一层轻薄的缓冲剂嵌入多孔基材深处。工作实施例包括1.25mg/cm2的硼酸钠、2mg/cm2的双(2-羟乙基)氨基(三羟甲基)甲烷或1mg/cm2的碳酸氢钠。然后,超声涂覆15mg/cm2的4臂-PEG-胺-HCl(分子量:10Kda),再超声涂覆18mg/cm2的4臂-PEG-SG(分子量:10Kda)。
拉绒构建体允许可交联活性物质独特地沉积到基质深处,最终产生具有增强粘附的高效止血剂。
Claims (16)
1.一种伤口敷料,所述伤口敷料包括熔喷基材,所述熔喷基材具有至少两个主面对表面和涂层,所述涂层被施加到所述主面对表面中的至少一个主面对表面,所述主面对表面选自共反应性水凝胶形成材料、一种或多种基于血浆的止血剂以及它们的组合,其中所涂覆的主面对表面是拉绒的。
2.根据权利要求1所述的伤口敷料,其中所述伤口敷料在拉绒之前具有在约0.30mm-1.5mm范围内的原始厚度和相对于所述原始厚度在大约50%-250%范围内的基质高度增加。
3.根据权利要求1所述的伤口敷料,其中所述伤口敷料在拉绒之前具有在约0.6mm-0.95mm范围内的原始厚度和相对于所述原始厚度在大约55%-175%范围内的基质高度增加。
4.根据权利要求1所述的伤口敷料,其中所述伤口敷料在拉绒之前具有在约0.85mm-0.90mm范围内的原始厚度和相对于所述原始厚度在大约125%-165%范围内的基质高度增加。
5.根据权利要求1所述的伤口敷料,所述伤口敷料具有在约140mg/cm3-250mg/cm3范围内的密度。
6.根据权利要求2所述的伤口敷料,所述伤口敷料具有约140mg/cm3-200mg/cm3的密度。
7.根据权利要求3所述的伤口敷料,所述伤口敷料具有约140mg/cm3-150mg/cm3的密度。
8.根据权利要求1所述的伤口敷料,所述伤口敷料具有孔,通过显微-CT分析测量,大多数孔在0.1mm-0.3mm的范围内。
9.根据权利要求1所述的伤口敷料,所述伤口敷料具有通过显微-CT分析测量的大约85%的总开口孔隙率。
10.根据权利要求1所述的伤口敷料,其中所述熔喷基材是可生物降解聚合物材料,所述可生物降解聚合物材料选自聚乙醇酸(PGA)、聚(乳酸-共-乙醇酸)(PLGA)、聚乳酸(PLA)、聚二氧六环酮(PDS)、己内酯/乙交酯聚酯、聚(己内酯-共-乙交酯)以及它们的组合。
11.根据权利要求1所述的伤口敷料,其中所述熔喷基材是乙交酯和ε-己内酯的共聚物。
12.根据权利要求1所述的伤口敷料,其中所述水凝胶形成材料各自为包含两个或更多个亲电子或亲核官能团的至少两种不同的多官能聚合物或聚合物前体。
13.根据权利要求20所述的伤口敷料,其中所述水凝胶形成材料中的至少一种水凝胶形成材料具有两个或更多个亲核官能团,所述两个或更多个亲核官能团与第二水凝胶形成材料上的亲电子官能团反应以形成共价键。
14.根据权利要求1所述的伤口敷料,其中所述止血剂选自具有止血活性的凝血酶原、凝血酶、纤维蛋白、纤连蛋白、因子(Factor)X/Xa、因子VII/VIIa、因子IX/IXa、因子XI/XIa、因子XII/XIIa、组织因子、血管性血友病因子、弹性蛋白、白蛋白、血小板表面糖蛋白、血管加压素和由类似物组成的血管加压素组、肾上腺素、选择素、纤溶酶原激活物抑制剂、血小板激活剂、合成肽以及它们的任何组合。
15.一种用于制备根据权利要求1所述的伤口敷料的方法,包括将微纤维熔喷为网状片材,将所述熔喷片材分层,粘合所述熔喷片材层,拉绒并且涂覆所述粘合的熔喷片材层的主暴露表面。
16.一种用于密封组织表面的方法,包括将根据权利要求1所述的伤口敷料施用在受伤的组织表面上。
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