CN116685328A - 用于组织损伤和伤口中的营养维持和废物清除的方法和组合物 - Google Patents
用于组织损伤和伤口中的营养维持和废物清除的方法和组合物 Download PDFInfo
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Abstract
描述了用于在组织损伤、疾病、手术或伤口部位引入营养支持材料和任选的废物清除材料的方法和组合物。这些方法和组合物可用于优化所述组织损伤、疾病、手术或伤口部位的组织愈合环境的目的。
Description
背景技术
组织损伤、疾病、手术或伤口的部位,比如在手术切口和解剖、骨折、肌腱和韧带撕裂、脊椎融合、关节重建、创伤、骨折或其他需要后续组织愈合的生理情况,可因初始创伤、疾病或损伤以及因手术过程比如骨膜剥离和电烙术的使用而急性损伤。因此,由损伤和手术引起的组织损伤会对组织愈合产生显著的负面影响。此外,损伤和手术经常发生在其中生物环境免疫豁免和血管化不足的解剖部位,比如关节内和周围以及椎间盘间隙,其另外延迟自然组织愈合。术后,新生血管和组织愈合向内生长的发生可能需要数周时间,在此期间存在组织存活的非最佳宿主环境。
组织损伤、疾病、手术或伤口部位的组织愈合一般地经宿主生物体内在的生物过程发生,包括形成血肿导致免疫细胞的浸润,最终导致经肉芽组织和愈合组织形成强健的新生血管。这些内在过程可能需要数天到数周时间来建立能持续地维持组织稳态的生物环境。通过干预比如手术以进行骨折稳定、成形重建以增强软组织缺损,或者通过手术植入或注射以提供另外的生物补充的骨或细胞移植,为愈合提供外在贡献。例如,一种常用的改善骨愈合的方法为在需要生物骨补充的部位手术植入自体骨移植物。移植细胞已经显示错综复杂地参与促进自体骨移植物的有效性。然而,从长骨和髂骨获得的自体骨髓抽吸物或骨移植物可含有仅为0.01%-0.001%的间充质干细胞——组织成功愈合的关键细胞。
术中细胞或骨移植物处理不佳,以及在完全建立内在生物支持之前植入到萎缩/生物学不佳的宿主部位,可导致干细胞损失和移植物死亡,且从而导致不完美的愈合率,比如在细胞扩增的矫形外科长骨和脊椎手术以及其他组织愈合和组织修复情况中所见的那些。这种情况经常导致移植物存活率、骨愈合率和相关的组织修复率下降。
本领域需要在组织损伤、疾病、手术、伤口和/或其他组织缺损的部位促进细胞愈合、存活和修复,可维持组织稳态直至内在生物过程可发挥相同的作用的方法和组合物。
发明内容
本发明基于发明人的理论,即细胞活力不佳,和/或由于缺乏局部组织稳态而无法触发再生表型,促进在细胞扩增的矫形外科长骨和脊椎手术以及其他组织愈合情况下所见的不完美愈合率。
一方面,提供用于补充组织存活的营养支持材料。材料包括a)用于控制营养物释放的缓慢洗脱载体;和b)包含葡萄糖的营养混合物;并且其中缓慢洗脱载体的释放半衰期在30分钟-14天之间。在某些实施方案中,营养支持材料为可植入或可注射的。在某些实施方案中,营养混合物含有粉状商业细胞培养基,比如DMEM、EMEM、RPMI、IMDM、Ham’s F10或Ham’s F12培养基粉末。在某些实施方案中,材料呈直径在1微米-5mm之间的微粒形式。在某些实施方案中,载体为载体聚合物基质,任选地为PLGA。
另一方面,提供补充与损伤、疾病或手术相关的组织存活的方法。方法包括将如本文所述的营养支持材料给予组织损伤、疾病、手术或伤口部位。在某些实施方案中,方法进一步包括在组织损伤、疾病、手术或伤口部位给予废物清除材料。在某些实施方案中,方法包括将营养支持材料,任选地与废物清除材料组合,与骨移植物一起给予。在其他实施方案中,方法包括给予营养支持材料,任选地与废物清除材料组合,与细胞疗法一起给予。
一方面,在组织损伤、疾病、手术或伤口部位增加组织愈合的方法包括在组织损伤、疾病、手术或伤口部位向需要它的受试者引入营养支持材料以提高组织在损伤环境中的存活率。在一个实施方案中,在组织损伤、疾病或伤口部位闭合之前的手术程序期间引入材料。
另一方面,在组织损伤、疾病、手术或伤口部位增加组织愈合的方法包括在组织损伤、疾病、手术或伤口部位向需要它的受试者引入废物清除材料以提高细胞在损伤环境中的存活率。在一个实施方案中,在组织损伤、疾病或伤口部位闭合之前的手术程序期间引入材料。
在仍然另一方面,在组织损伤、疾病、手术或伤口部位增加组织愈合的方法包括在组织损伤部位、手术或伤口部位向需要它的受试者引入营养支持材料和废物清除材料以提高细胞在损伤环境中的存活率。在一个实施方案中,在组织损伤、疾病或伤口部位闭合之前的手术程序期间引入材料。
在仍然另一方面,用于在组织损伤、疾病、手术或伤口部位增加愈合的组合物包含在适合于递送至组织损伤、疾病、手术或伤口部位的生理学上可接受的递送系统中的有效量的营养支持材料。
在仍然另一方面,用于在组织损伤、疾病、手术或伤口部位增加愈合的组合物包含在适合于递送至组织损伤、疾病、手术或伤口部位的生理学上可接受的递送系统中的有效量的废物清除材料。
另一方面,用于在组织损伤、疾病、手术或伤口部位增加愈合的组合物包含在适合于递送至组织损伤、疾病、手术或伤口部位的生理学上可接受的递送系统中的有效量的营养支持材料和废物清除材料。
仍然另一个方面为用于植入到组织损伤、疾病、手术或伤口部位中的组合物,其用能够在所述植入部位产生其预期效果的营养支持材料和/或废物清除材料涂覆或浸渍。
在以下对其优选实施方案的详细描述中进一步描述了这些组合物和方法的仍然其他方面和优点。
附图说明
图1A-1C.负载Dulbecco改良Eagle培养基(DMEM)的营养聚乳酸-乙醇酸共聚物(PLGA)微粒的制造方法的一个实例。图1A.显示初级乳液的形成、在涡旋下将其滴加到0.5%聚乙烯醇(PVA)中以形成次级乳液以及最终洗涤以获得硬化微粒的分步图解。图1B.在次级乳液步骤完成之后,硬化微粒通过重力沉降。图1C.微粒的40x放大暗场显微术显示与颜色为白色的天然PLGA形成对比,由嵌入PLGA球体内的DMEM粉末产生着色。
图2A-2C.实验数据证实人体骨髓间充质干细胞(hBM MSC)的细胞存活所需要的必需营养物。使用负载有Dulbecco改良Eagle培养基(DMEM)的PLGA制造颗粒,DMEM为一种标准化细胞培养基营养组合物。图2A.使用hBM-MSC在补充有营养颗粒相对于没有颗粒的缓冲盐水中进行时间点活力。在10小时时,光学显微术显示存在营养颗粒情况下的健康活细胞(图2B)相对于不存在颗粒情况下几乎完全死亡的细胞(图2C)。
图3.用于在存在相对于不存在置于孔洞插入物中释放营养和/或清除废物的微粒的情况下体外测试细胞活力的方案的一个实例实施方案。
图4.将营养支持和/或废物处理材料(在这种情况下为微粒)引入到组织损伤或伤口部位中用于改善组织愈合的实例实施方案。
图5.显示DMEM基蜡涂覆固体核心微粒的洗脱曲线的图表,显示具有合乎期望的初始爆裂释放的缓释曲线。
图6.使用原代骨髓来源的人类间充质干细胞(hBM-MSC)作为模型细胞类型,可使用控释营养微粒维持这些细胞类型的体外活力。当在培养物中与胎牛血清(FBS)一起使用时,可见协同作用。
图7.尽管炭基废物清除微粒本身显示最小的细胞活力作用,但当与控释营养微粒一起使用时,其在体外促进细胞活力方面显示协同作用。
图8.存活3周的人体骨髓间充质干细胞(hBM-MSC)的分化测定显示,当与营养洗脱微粒共培养时,干细胞多能性(成脂、软骨和成骨分化)的维持程度至少相当于10%胎牛血清(FBS)存活的hBM-MSC(阳性对照)。这表明营养补充可以改善。相比之下,未分化的hBM-MSC(阴性对照)显示低水平的分化标志物染色。上图显示定性油红-O、番红-O和茜素红单层染色,分别用于检测成脂、软骨和成骨分化。下图显示保留染色的吸光度量化。
图9.大鼠腰椎后外侧脊椎融合模型中的放射照相证据表明,与使用空白颗粒(B)相比较,在8周时与髂骨自体移植物一起提供营养微粒改善骨融合(A)。白色箭头是指手术级别L4-L5。
具体实施方式
目前描述的方法和组合物通过将营养支持和/或毒素处理材料引入到损伤、手术和/或其他伤口部位以提高局部细胞和组织存活率来解决本领域的这一需求。通过直接植入或注射到损伤或手术部位进行局部营养补充和废物清除为一种支持受损组织的活力和愈合的新技术,并且可对未来的手术实践以及在其他医学实践领域产生显著影响。
这些方法和组合物具体地讲为人类在手术中的应用提供改善骨和软组织愈合的潜力。在矫形外科手术领域,尤其是在脊椎、重建关节和创伤应用领域,存在直接和固有的从实验室到临床的相关性,其中外科医生经常遇到失去活力的组织缺损并面临在不佳的生物环境中再生组织的困难。由于专注于改善骨移植和骨愈合,这些方法和组合物与在脊椎、创伤和重建矫形外科方面改善功能、消除疼痛和恢复灵活性密切相关。本发明在颅面重建、骨折愈合、脊椎融合、矫形外科软组织愈合(肌腱、肌肉、韧带、椎间盘)、手术伤口愈合、创伤性伤口愈合和内脏器官愈合方面具有广泛的潜在应用,但不限于此。除用于骨移植之外,该技术的组合物和方法还可用于微粒植入、注射、喷涂、植入物上的涂覆、整体植入等。
在一些实施方案中,这些用于通过提供营养和废物处理来刺激组织愈合的方法和组合物消除了对当以非生理剂量在医学或手术中使用时具有造成伤害的可能性的生物活性药物和分子的需要。
因此,一方面,如以下详细描述的,提供一种用于当置于损伤、缺损或伤口的直接部位时增加骨缺损、损伤或伤口部位愈合的组合物。一方面,组合物在适合于直接递送至缺损、损伤或伤口部位的生理学上可接受的递送系统中包含有效量的营养支持材料。另一方面,组合物在用于直接递送至缺损、损伤或伤口部位的生理学上可接受的递送系统中包含有效量的废物处理材料。另一方面,组合物在用于直接递送至缺损、损伤或伤口部位的生理学上可接受的递送系统中包含有效量的营养支持材料和废物处理材料。
另一方面,如以下详细描述的,增加组织缺损、移植物、损伤、手术部位或伤口愈合的方法包括在组织缺损、移植物、损伤部位、手术部位或伤口引入营养支持材料和/或废物处理材料以提高细胞在伤口环境中的存活率。
I.在方法和组合物中有用的成分和定义
A.营养和营养补充材料
在医生当中,一致认为营养在损伤组织的修复、再生和愈合中具有高度重要性。已知适当的膳食营养改善组织愈合,部分地证据为这样一个事实,即在广泛的创伤或烧伤中,由于愈合反应产生的身体每日热量需求可能会增加数倍。进一步的证据存在于肾或肝功能受损或血管疾病的病例中,这些疾病导致电解质失衡和组织营养递送不佳,且从而导致相关的伤口愈合反应不佳。细胞营养的重要性跨越医学和外科学科;例如,在矫形外科医生当中,一致认为在因恶性肿瘤或终末期多器官疾病或饥饿而严重消瘦的患者发生的骨折基本上不会愈合。整形外科医生经常强调营养在伤口和慢性溃疡管理中的重要性。管理截肢和肢体坏疽患者的血管外科医生显示,当营养概况在围手术期得以优化时愈合有所改善,并且已经显示营养状况为降低手术风险和改善效果的预测因素。
本发明人证实,组织愈合,无论是作为对手术干预、损伤还是疾病的反应,也受益于对受影响部位的直接营养补充。然而,手术或损伤的组织床由一定程度的局部组织失活组成,这不利于来自宿主生物体的内在营养递送。因此,本文所述的方法和组合物经直接施用/植入过程为受损组织提供营养,目的是改善医学和外科学科的愈合效果。
本文提供的“营养支持材料”包含“营养混合物”。如本文使用的“营养混合物”意指含有多种糖、氨基酸、维生素、脂肪酸、矿物质、盐和核酸中的一种或混合物的保持生理pH的组合物。在某些实施方案中,营养混合物至少含有葡萄糖。在某些实施方案中,营养混合物可包含pH缓冲盐、钠和钾盐、葡萄糖、硫胺素、核黄素、烟酸、泛酸、吡哆辛、生物素、叶酸类、钴胺素、维生素A、维生素D、维生素E、维生素K、维生素C、丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸、牛磺酸、葡萄糖醛酸内酯、肉毒碱、肌酸、丙酮酸钠、腺嘌呤、腺苷、鸟嘌呤、胞嘧啶、胸腺嘧啶、尿嘧啶、膳食脂肪酸(长度为4-24个碳的饱和、单不饱和及多不饱和脂肪酸,比如棕榈酸、硬脂酸、油酸、亚油酸、亚麻酸、花生四烯酸、二十碳五烯酸、二十二碳六烯酸、ω-3脂肪酸和ω-6脂肪酸)、胆固醇、镁、钾、钙、硼、锌、铜、铁、磷、钒、锶、硅、硒、镍或锰。在另一个实施方案中,营养混合物可包括用于维持组织稳态所需要的所有必需氨基酸、糖、维生素、核酸和缓冲盐。
在另一个实施方案中,营养混合物源于细胞培养基配方,比如用于Dulbecco改良Eagle培养基(DMEM)的ATCC 30-2002配方,包括无机盐CaCl2、Fe(NO3)3·9H2O、MgSO4、KCl、NaHCO3、NaCl、NaH2PO4·H2O和/或氨基酸L-精氨酸·HCl、L-胱氨酸·2HCl、L-谷氨酰胺、甘氨酸、L-组氨酸·HCl·H2O、L-异亮氨酸、L-亮氨酸、L-赖氨酸·HCl、L-甲硫氨酸、l-苯丙氨酸、L-丝氨酸、L-苏氨酸、L-色氨酸、L-酪氨酸·2Na·2H2O、L-缬氨酸和/或维生素比如氯化胆碱、叶酸、肌醇烟酰胺、d-泛酸、(半钙)吡哆辛·HCl、核黄素、硫胺素·HCl。仍然其他成分包括d-葡萄糖、酚红、钠盐、丙酮酸钠。其他营养成分可包括其他已知培养基配方的成分,比如RPMI 1640、EMEM或其他的其细胞培养基配方变体。可将已知细胞培养基成分的各种混合物引入到营养材料混合物中。然而,众所周知的细胞培养基为已知对体外细胞生长安全有效的方便混合物。本文描述了一些常用的细胞培养基。这些培养基可以粉状形式自FisherScientific和其他供应商获得。在某些实施方案中,营养混合物作为粉状细胞培养基提供。在其他实施方案中,营养混合物作为液体或半固体细胞培养基提供。
Eagle最小必需培养基(EMEM)为首先广泛使用的培养基之一,并且由Harry Eagle从更简单的基础培养基(BME)配制。EMEM含有平衡盐溶液、非必需氨基酸和丙酮酸钠。
Dulbecco改良Eagle培养基(DMEM)具有浓度为EMEM的几乎两倍的氨基酸和量为EMEM的四倍的维生素以及硝酸铁、丙酮酸钠和一些补充氨基酸。初始配方含有1,000mg/L的葡萄糖,并且首次报道用于培养小鼠胚胎细胞。已经证明4500mg/L葡萄糖的另一变体对于各种类型细胞的培养为最佳的。DMEM为一种基础培养基并且不含蛋白或生长促进剂。因此,其需要补充以成为“完全”培养基。最常补充有5-10%的胎牛血清(FBS)。
RPMI-1640为一种对哺乳动物细胞,尤其是造血细胞具有广泛应用的通用培养基。RPMI-1640为在纽约州水牛城的Roswell Park Memorial Institute(RPMI)开发。RPMI-1640为McCoy’s 5A的改良,并且是为长期培养外周血淋巴细胞而开发。RPMI-1640使用碳酸氢盐缓冲系统,并且与大多数哺乳动物细胞培养基的不同之处在于其典型的pH 8配方。RPMI-1640支持各种细胞在悬浮液中的生长和作为单层生长。
Ham的营养混合物最初开发是为支持中国仓鼠卵巢(CHO)细胞的克隆性生长。对初始配方存在许多改良,包括Hams的F-12培养基,这是一种比初始F-10更复杂的配方,适合于无血清繁殖。根据培养的细胞类型,配制混合物补充或不补充血清。
Ham’s F-10:其已经显示支持人类二倍体细胞的生长,例如人类成纤维细胞和用于染色体分析的白细胞。
Ham’s F-12:其已经显示支持原代大鼠肝细胞和大鼠前列腺上皮细胞的生长。补充有25mM HEPES的Ham’s F-12提供更加最佳的缓冲。
Ham’s F-12的Coon’s改良:与F-12相比较,其由几乎两倍量的氨基酸和丙酮酸盐组成,并且还包括抗坏血酸。其是为培养通过病毒融合产生的杂交细胞而开发。
DMEM/F12:其为DMEM和Ham’s F-12的混合物,并且是一种极其丰富和复杂的培养基。其支持血清和无血清配方两者中广泛细胞类型的生长。HEPES缓冲液以15mM的最终浓度包含在配方中,以补偿通过消除血清而引起的缓冲能力损失。
Iscove改良Dulbecco培养基(IMDM)为一种高度富集的合成培养基,非常适合于快速增殖、高密度细胞培养。IMDM为含有硒的改良的DMEM,并且与DMEM相比较,其具有另外的氨基酸、维生素和无机盐。其具有硝酸钾而不是硝酸铁,并且还含有HEPES和丙酮酸钠。其配制用于淋巴细胞的生长,例如单核细胞分化成巨噬细胞和杂交瘤。
B.废物去除材料
除营养提供之外,废物去除为在不佳的宿主环境中保持细胞稳态的一个补充因素。炭作为一种实施方案已广泛用于药物解毒的医学应用和体外植物细胞培养的科学研究中。有大量证据表明,活性炭对植物细胞培养具有积极作用,这可能是由于抑制性化合物在培养基中的吸附和毒性代谢物的隔离所致。然而,炭还没有探索作为动物细胞培养的辅助物或作为促进手术应用的体内细胞/组织存活的手段。先前的研究证实,涂覆活性炭具有选择性吸附小分子的益处,同时对蛋白和其他大分子的影响最小。活性炭对通常在尿液中排泄的毒素和废物也具有高亲和力,而对离子几乎没有亲和力,从而避免小的荷电营养颗粒的不必要吸附和对局部电解质平衡的不必要影响。尽管葡聚糖涂覆的炭微粒在商业上可自由获得,但葡聚糖已经显示会引起初期和二期止血的紊乱,由于出血的风险这将禁止其在某些手术应用中使用。相反,生物相容性涂层可助于提高废物清除材料的体内效用。在一个实施方案中,使用纤维素涂层制造生物相容性涂覆炭可克服这些限制,因为纤维素不仅会降低炭的孔隙率以防止大分子吸附,而且还会用作促凝剂助于止血。因此,具有生物相容性纤维素涂层的活性炭为可用于本发明组合物或方法的废物清除材料。
在仍然另一个实施方案中,废物清除材料为类黄酮,比如本领域所述的类黄酮。参见例如Tremi,J和Smejkal,K,Flavonoids as Potent Scavengers of HydroxylRadicals,2016Comprehen.Rev.,15(4):820-8738,通过参考结合到本文中。
C.适合于直接递送至组织损伤、疾病、手术或伤口部位的递送媒介物
营养支持材料或废物处理材料的另一种成分为适合于释放营养混合物/废物清除材料的递送媒介物。在一个实施方案中,递送媒介物为关于预期给予途径和标准药物实践选择的合适的药物赋形剂、稀释剂、缓冲液或载体。在一个实施方案中,可用于将营养支持材料和/或废物处理材料调节至生理pH以应用于骨损伤、缺损或症状中和周围的碳酸盐缓冲液或其他生理学上有用且安全的缓冲液为有用的。一方面,将载体或缓冲液调节至pH为约7.4。
营养和/或废物清除补充的递送可以用于植入的固体、用于注射的液体、粉末、片状物、颗粒、微粒、纳米颗粒、胶囊、乳膏、凝胶、乳液、糊状物、涂层、现有植入物或组织的浸渍、其组合,或含有植入营养/废物清除材料的浸渍装置,或用于营养补充剂/废物清除材料的任何生物学上可接受的递送装置的形式实现。组合物可单独局部给予(以生理盐水等作为培养基),或者除各种生长因子之外可含有选自支架、胞外基质蛋白、凝胶化材料和增稠剂的一种或两种或更多种递送媒介物。例如,当使用生理盐水等局部给予时,营养成分/废物清除成分可到达整个骨髓,而当使用支架时,这些组成可限于给定的骨区域,并且仅改善所需部分的骨质。
在一个实施方案中,在人类手术应用中使用微粒补充来改善组织愈合和细胞活力为另一种递送机制。例如,经微粒引入确保细胞稳态的关键成分(具体地讲,营养补充和废物处理)改善成骨反应,并从而提高需要这样做的解剖区域中的骨愈合和融合率。
在美国专利第10,335,498号中描述了多种这样的微粒,通过参考结合至本文中。在一个实施方案中,递送媒介物包含利用例如聚乙烯亚胺(PEI)、壳聚糖、环糊精或树状物的阳离子聚合物微粒。在一个实施方案中,递送媒介物包含非阳离子聚合物,例如二油酰基磷脂酰乙醇胺(DOPE)、胆固醇、聚酰胺胺(PAMAM)或泊洛沙姆。在一个实施方案中,营养补充材料和/或废物清除材料与阳离子聚合物复合并包封到微粒例如PLGA中。当在骨缺损、损伤或伤口部位提供时,这些颗粒可进入到细胞中用于组织工程应用。在一个实施方案中,采用PLGA颗粒以增加包封频率,尽管与聚L-赖氨酸(PLL)形成复合物也可增加包封效率。其他阳离子材料,例如N-[1-(2,3-二油酰氧基)丙基]-N,N,N-三甲基铵(DOTMA)、3-β-[N-(N,N’-二甲基氨基乙烷)氨基甲酰基]胆固醇(DC-Chol)或溴化鲸蜡基三甲基铵(CTAB),可用于制备微粒。聚合物的共混物也可用于调节包封效率和营养洗脱特性。
在一个实施方案中,递送媒介物为非生物活性或最低生物活性的。一个实施方案包括无机微粒,例如磷酸钙或二氧化硅颗粒;聚合物,包括但不限于PLGA、聚乳酸(PLA)、具有不同分子量(例如2、22和25kDa)的线性和/或分支PEI、树状物比如PAMAM和聚甲基丙烯酸酯;脂质,包括但不限于阳离子脂质体、阳离子乳液、1,2-二油酰基-3-三甲基铵-丙烷(DOTAP)、DOTMA、DMRIE、DOSPA、二硬脂酰磷脂酰胆碱(DSPC)、DOPE或DC-chol;肽基载体,包括但不限于聚L-赖氨酸或鱼精蛋白;或聚(β-氨基酯)、壳聚糖、PEI-聚乙二醇、PEI-甘露糖-右旋糖、DOTAP-胆固醇或PEI-PEG、PEI-PEG-甘露糖、葡聚糖-PEI、OVA缀合物、PLGA微粒或用PAMAM涂覆的PLGA微粒。
在一个实施方案中,递送媒介物为含糖聚合物基递送媒介物,即聚(含糖酰胺胺)(PGAA),其具有与各种多核苷酸类型复合并形成微粒的能力。这些材料通过将各种碳水化合物(D-葡萄糖二酸(D)、内消旋-半乳糖二酸(G)、D-甘露糖(mannarate)(M)和L-酒石酸(T))的甲酯或内酯衍生物与一系列低聚乙烯胺单体(含有1-4个之间的乙烯胺)聚合而产生(Liu和Reineke,2006)。由聚合物重复单元中的这些碳水化合物和4种乙烯胺组成的子集产生这些出色的递送效率。
在一个实施方案中,递送媒介物包括阳离子脂质,例如DOTMA、2,3-二油酰氧基-N-[2-精胺甲酰胺]乙基-N,N-二甲基-1-丙铵三氟乙酸盐(DOSPA,Lipofectamine);DOTAP;N-[1-(2,3-二肉豆蔻酰氧基)丙基];N,N-二甲基-N-(2-羟乙基)溴化铵(DMRIE)、DC-Chol;双十八烷基酰胺基甘油基精胺(DOGS,Transfectam);或双十八烷基二甲基溴化铵(DDAB)。阳离子脂质的荷正电亲水性头基通常由单胺(比如叔胺和季胺)、聚胺、脒鎓或胍鎓基团组成。已经开发了一系列吡啶鎓类脂质(Zhu等人,2008;van der Woude等人,1997;Ilies等人,2004)。除吡啶鎓阳离子脂质之外,其他类型的杂环头基包括咪唑、哌嗪和氨基酸。阳离子头基的主要功能为通过静电相互作用将荷负电核酸凝聚为略荷正电的纳米颗粒,导致增强细胞摄取和内体逃逸。
具有两个线性脂肪酸链的脂质,比如DOTMA、DOTAP和SAINT-2或DODAC,可用作递送媒介物,以及四烷基脂质链表面活性剂,即N,N-二油酰基-N,N-二甲基氯化铵(DODAC)的二聚体。所有反式取向脂质,无论其疏水链长度如何(C16:1、C18:1和C20:1),与其顺式取向对应体相比较均可提高转染效率。
可用作递送媒介物的阳离子聚合物的结构包括但不限于线性聚合物比如壳聚糖和线性聚(乙烯亚胺),分支聚合物比如分支聚(乙烯亚胺)(PEI)、环状聚合物比如环糊精,网络(交联)型聚合物比如交联聚(氨基酸)(PAA)和树状物。树状物由中心核心分子组成,若干个高度分支的臂从其“生长”以形成具有对称或不对称方式的树状结构。树状物的实例包括聚酰胺胺(PAMAM)和聚丙烯亚胺(PPI)树状物。
DOPE和胆固醇为用于制备阳离子脂质体的常用中性辅助脂质。分支PEI-胆固醇水溶性脂质聚合物缀合物自组装成阳离子胶束。也可使用非离子聚合物Pluronic(泊洛沙姆)和SP1017,其为Pluronics L61和F127的组合。
在一个实施方案中,采用PLGA颗粒以提高包封效率,尽管与PLL形成复合物也可提高包封效率。其他阳离子材料,例如PEI、DOTMA、DC-Chol或CTAB,可用于制备微粒。
在一个实施方案中,不采用递送媒介物,例如单独或与支架一起采用营养材料。
用于将营养补充/废物清除材料递送至骨缺损部位、损伤或手术部位的支架的示例性特性包括生物相容性、生物降解性、合适的机械特性和支架结构中的至少一种。生物相容性支架或组织工程构建体不会引发免疫反应或引发可忽略的免疫反应。可生物降解的支架允许在植入部位的组织再生。支架的机械特性与其待植入的解剖部位一致。例如,骨或软骨支架必须具有足够的机械完整性,以从植入时间到完成重塑过程发挥作用。支架可具有相互连接的孔隙结构和/或高孔隙率。
三组单独的生物材料,即陶瓷、合成聚合物和天然聚合物,通常用于支架制造。尽管通常不用于软组织再生,但陶瓷支架比如羟基磷灰石(HA)和磷酸三钙(TCP)已广泛用于骨再生应用。陶瓷支架一般地特征为高机械刚度、非常低的弹性和坚硬、脆性表面。从骨的角度来看,由于其化学和结构与天然骨矿物相的相似性,因此它们表现出优异的生物相容性。成骨细胞与陶瓷的相互作用对骨再生很重要,因为已知陶瓷可增强成骨细胞分化和增殖。
如上所述,已经使用了许多合成聚合物,包括聚苯乙烯、聚1-乳酸(PLLA)、聚乙醇酸(PGA)和聚dl-乳酸-乙醇酸共聚物(PLGA)。
另一个递送媒介物实施方案涉及使用生物材料作为支架生物材料。生物材料比如胶原蛋白、各种蛋白聚糖、海藻酸盐基基质和壳聚糖,均已用于产生用于组织工程的支架。与合成聚合物基支架不同,天然聚合物为生物活性的,并且一般地促进优异的细胞粘附和生长。此外,天然聚合物也为可生物降解的,并且因此允许宿主细胞随着时间的推移产生其自己的胞外基质。
胶原蛋白和胶原蛋白-GAG(CG)支架可通过物理和化学交联来改变。胶原蛋白-羟基磷灰石(CHA)支架可用于骨缺损。用于聚合物的合适的生物相容性材料包括但不限于聚乙酸或聚乙醇酸及其衍生物、聚原酸酯、聚酯、聚氨酯、聚氨基酸比如聚赖氨酸、乳酸/乙醇酸共聚物、聚酸酐和离子交换树脂比如磺化聚四氟乙烯、聚二甲基硅氧烷(硅橡胶)或其组合。
在一个实施方案中,复合物嵌入或应用于材料,包括但不限于泊洛沙姆水凝胶、聚丙烯酰胺、聚(2-羟乙基甲基丙烯酸酯)、羧基乙烯聚合物(例如Carbopol 934,GoodrichChemical Co.)、纤维素衍生物,例如甲基纤维素、乙酸纤维素和羟丙基纤维素、聚乙烯吡咯烷酮或聚乙烯醇或其组合中。
在一些实施方案中,生物相容性聚合物材料衍生于可生物降解聚合物,比如胶原蛋白,例如羟基化胶原蛋白、纤维蛋白、聚乳酸-聚乙醇酸或聚酸酐。其他实例非限制性地包括任何生物相容性聚合物,无论亲水、疏水还是两亲性的,比如乙烯乙酸乙烯酯共聚物(EVA)、聚甲基丙烯酸甲酯、聚酰胺、聚碳酸酯、聚酯、聚乙烯、聚丙烯、聚苯乙烯、聚氯乙烯、聚四氟乙烯、N-异丙基丙烯酰胺共聚物、聚(环氧乙烷)/聚(环氧丙烷)嵌段共聚物、聚(乙二醇)/聚(D,L-丙交酯-共-乙交酯)嵌段共聚物、聚乙交酯、聚丙交酯(PLLA或PDLA)、聚(己内酯)(PCL)或聚(二氧环己酮)(PPS)。
在另一个实施方案中,生物相容性材料包括聚对苯二甲酸乙二醇酯、聚四氟乙烯、聚环氧乙烷和聚环氧丙烷的共聚物、聚乙醇酸和聚羟基链烷酸酯的组合、明胶、海藻酸盐、聚3-羟基丁酸酯、聚4-羟基丁酸酯和聚羟基辛酸酯以及聚丙烯腈聚氯乙烯。
在一个实施方案中,用于不同聚合物的生物相容性材料源于分离的胞外基质(ECM)。ECM可从各种细胞群、组织和/或器官的内皮层中分离,例如任何器官或组织来源,包括温血脊椎动物的皮肤真皮、肝脏、消化、呼吸、肠、泌尿或生殖道。本发明中采用的ECM可来自多种来源的组合。分离的ECM可制备为片状、颗粒形式、凝胶形式等。
生物相容性支架聚合物可包含丝、弹性蛋白、几丁质、壳聚糖、聚(d-羟基酸)、聚(酸酐)或聚(原酸酯)。更特别地,生物相容性聚合物可形成聚乙二醇、聚(乳酸)、聚(乙醇酸)、乳酸和乙醇酸的共聚物、乳酸和乙醇酸与聚乙二醇的共聚物、聚(E-己内酯)、聚(3-羟基丁酸酯)、聚(对二氧环己酮)、聚富马酸丙二醇酯、聚(原酸酯)、多元醇/双烯酮缩醛加成聚合物、聚(癸二酸酐)(PSA)、聚(羧基双羧基苯氧基苯氧基己酮(PCPP)、聚[双(对羧基苯氧基)甲烷](PCPM)、SA、CPP和CPM的共聚物、聚(氨基酸)、聚(伪氨基酸)、聚磷腈、聚[(二氯)磷腈]或聚[(有机)磷腈]的衍生物、聚羟基丁酸或S-己酸、聚丙交酯-乙交酯共聚物、聚乳酸、聚乙二醇、纤维素、氧化纤维素、海藻酸盐、明胶或其衍生物。
因此,用作支架的聚合物可由广泛范围的任何材料形成,包括聚合物,包括天然存在的聚合物、合成聚合物或其组合。在一个实施方案中,支架包含可生物降解聚合物。在一个实施方案中,可对天然存在的可生物降解聚合物进行改性以提供衍生于该天然存在聚合物的合成可生物降解聚合物。在一个实施方案中,聚合物为聚(乳酸)(“PLA”)或聚乳酸-乙醇酸共聚物(“PLGA”)。在一个实施方案中,支架聚合物包括但不限于海藻酸盐、壳聚糖、聚(2-羟乙基甲基丙烯酸酯)、木葡聚糖、2-甲基丙烯酰氧基乙基磷酰胆碱的共聚物、聚(乙烯醇)、硅酮、疏水性聚酯和亲水性聚酯、聚丙交酯-乙交酯共聚物、N-异丙基丙烯酰胺共聚物、聚(环氧乙烷)/聚(环氧丙烷)、聚乳酸、聚(原酸酯)、聚酸酐、聚氨酯、2-羟乙基甲基丙烯酸酯和甲基丙烯酸钠的共聚物、磷酰胆碱、环糊精、聚砜和聚乙烯吡咯烷酮、淀粉、聚-D,L-乳酸-对二氧环己酮-聚乙二醇嵌段共聚物、聚丙烯、聚(对苯二甲酸乙二醇酯)、聚四氟乙烯、聚ε-己内酯或交联壳聚糖水凝胶。
在某些实施方案中,营养支持材料采用缓慢洗脱载体来控制营养混合物的释放,使得释放半衰期在约30分钟-14天之间,包括端点。在某些实施方案中,释放半衰期在1小时-7天之间。在其他实施方案中,释放半衰期在1小时-24小时之间。在一些实施方案中,释放半衰期在1天-14天之间。在一些实施方案中,释放半衰期30分钟-10小时之间。在一些实施方案中,释放半衰期为约30分钟、1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时、13小时、14小时、15小时、16小时、17小时、18小时、19小时、20小时、21小时、22小时、23小时或24小时。在其他实施方案中,释放半衰期为约1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天或14天。缓慢洗脱载体通常由膜或基质制成。基质型配方由可溶胀亲水性聚合物或非可溶胀亲脂性赋形剂如蜡和脂质制备。用于缓慢洗脱系统的聚合物为本领域已知的,并且包括本文所述的那些,包括聚乳酸-乙醇酸共聚物(PLGA)、聚(乳酸)(PLA)和聚(二醇酸)(PGA)。参见du Toit LC,Choonara YE,Kumar P,Pillay V.Polymeric networks for controlled release of drugs:a patentreview.Expert Opin Ther Pat.2016Jun;26(6):703-17.Epub 2016Apr 27,其通过参考结合至本文中。迄今,聚乳酸-乙醇酸共聚物(PLGA)为控释系统中最众所周知和广泛应用的聚合物。该种合成聚合物由于其生物相容性、生物降解性和有利的释放动力学而取得巨大成功,但也面临蛋白递送的稳定性问题。聚(乙醇酸)(PGA)和聚(乳酸)(PLA)以及共聚物聚乳酸-乙醇酸共聚物(PLGA)为可生物降解的合成聚合物,它们在20世纪60年代作为手术缝合线而发现。这些聚合物作为手术缝合线的成功开发导致它们用作聚合物生物材料的扩展。从那时起,共聚物就被确定为用于控释系统的最成功和广泛研究的聚合物,并认为是用于控制递送系统的可生物降解聚合物的“金标准”。PLGA已用于释放广泛范围的小分子药物、肽和蛋白,包括生育调节激素、生长激素、类固醇激素、抗炎药物、细胞因子、化疗药物、抗生素、麻醉拮抗剂、胰岛素和疫苗。与其他已研究用于控释的聚合物相比较,PLGA相对易于加工成不同的装置形态,比如可注射的微米/纳米球。参见Hines,Daniel J和David LKaplan.“Poly(lactic-co-glycolic)acid-controlled-release systems:experimentaland modeling insights.”Critical reviews in therapeutic drug carrier systems第30卷,3(2013):257-76,其通过参考结合至本文中。
如本文使用的术语“微粒”是指尺寸为约0.1μm-约5mm、约1μm-约100μm、约0.5μm-约50μm、0.5μm-约20μm的颗粒,尺寸为约1μm-约10μm、尺寸为约5μm的颗粒或其混合物。所有范围包括端点及其间的所有整数。
如本文使用的术语“纳米颗粒”是指尺寸为约0.1nm-约1μm、1nm-约1μm、约10nm-约1μm、约50nm-约1μm、约100nm-约1μm、约250-900nm或有利地约600-800nm的颗粒。所有范围包括端点及其间的所有整数。
通过各种熔融技术制备的脂质载体中常用的材料为蜂蜡和巴西棕榈蜡。这些蜡含有大量的化学物质,比如甘油酯、脂肪酸、脂肪醇及其酯类。这些广泛用作缓释珠粒、片剂、悬浮液、植入物和微胶囊设计中的释放延迟剂(涂层)。蜡的优点包括在各种pH和湿度水平下具有良好的稳定性、由于其非可溶胀和不溶于水的性质所致在人体中得到确认的安全应用、对胃肠道中的食物影响最小以及没有剂量倾卸。在一个实施方案中,载体为至少50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或高达100%的巴西棕榈蜡或蜂蜡。参见Shaki,Hossein&Ganji,Fariba&Vasheghani-Farahani,Ebrahim&Shojaosadati,Seyed.(2009).Sustainedrelease of KCl from Beeswax/Carnauba wax microparticles,其通过参考结合至本文中。
采用廉价但安全的生物材料嵌入废物清除材料并以控制方式释放营养补充解决了其他方法存在的高成本和安全性问题。因此,将营养补充和废物清除直接应用于手术修复、骨损伤、伤口等部位的体内方法将进一步显著降低治疗成本。在美国专利申请出版物,比如第2009/0155216、US2019/0144856号和美国专利第6,811,776和第9,180,000号,以及本文公开的其他参考文献中描述了仍然其他的递送媒介物。
在以下描述的实施方案中,递送媒介物的一个实施方案为聚乳酸-乙醇酸共聚物(PLGA)聚合物,由于其有利的生物相容性、生物降解性及其提高体内寿命的相对疏水性,其为用于产生药物或因子洗脱生物材料的最广泛使用的包封剂。此外,其还被美国食品药品监督管理局和欧洲药品管理局批准用于人类。因此,PLGA认为是用于根据本文所述方法提供营养洗脱的有利支架材料。在一个实施方案中,采用PLGA颗粒以提高包封频率,尽管与PLL形成复合物也可提高包封效率。其他阳离子材料,例如PEI、DOTMA、DC-Chol或CTAB,可用于制备微粒。
其他生物相容性材料包括呈水凝胶或其他多孔材料形式的合成聚合物,例如可渗透的配置或形态,比如聚乙烯醇、聚乙烯吡咯烷酮和聚丙烯酰胺、聚环氧乙烷、聚(2-羟乙基甲基丙烯酸酯);天然聚合物比如树胶和淀粉;合成弹性体比如硅橡胶、聚氨酯橡胶;和天然橡胶,并且包括聚[α(4-氨基丁基)]-1-乙醇酸、聚环氧乙烷(Roy等人,2003)、聚原酸酯(Heller等人,2002)、丝蛋白-弹性蛋白样聚合物(Megeld等人,2002)、海藻酸盐(Wee等人,1998)、EVAc(聚乙烯-乙烯乙酸酯共聚物、微球比如聚(D,L-丙交酯-共-乙交酯)共聚物和聚(L-丙交酯)、聚(N-异丙基丙烯酰胺)-b-聚(D,L-丙交酯)、大豆基质比如与乙二醛交联并用生物活性填充剂增强的大豆基质,例如羟基磷灰石、聚(ε-己内酯)-聚(乙二醇)共聚物、聚(丙烯酰氧基羟乙基)淀粉、聚赖氨酸-聚乙二醇、琼脂糖水凝胶或脂质微管-水凝胶。
在一个实施方案中,可采用以下聚合物,例如天然聚合物,比如淀粉、几丁质、糖胺聚糖,例如透明质酸、硫酸皮肤素和硫酸软骨素,以及微生物聚酯,例如羟基链烷酸酯,比如羟基戊酸酯和羟基丁酸酯共聚物,以及合成聚合物,例如聚(原酸酯)和聚酸酐,并且包括乙交酯和丙交酯的均聚物和共聚物(例如聚(L-丙交酯)、聚(L-丙交酯-共-D,L-丙交酯)、聚(L-丙交酯-共-乙交酯)、聚乙交酯和聚(D,L-丙交酯)、聚(D,L-丙交酯-共乙交酯)、聚(乳酸共赖氨酸)和聚己内酯。
本发明的组合物也可用于在生物相容性有机或无机基质中给予,包括但不限于胶原蛋白或纤维蛋白原基质。设想这种基质可在适当的配方中用作组合物的载体,或者可通过增强组合物的作用来助于促进组织愈合。
递送媒介物也可为涂覆有营养材料(例如作为载体内的微粒)和/或废物清除材料的骨修复装置或植入物。合适的装置和植入物例如在美国专利申请公开号2019/0209327和US 2019/0021862等中进行了描述,并且通过参考结合至本文中。
一旦用合适的递送媒介物制备营养补充剂/废物清除材料,例如包封于微粒中,则将组合物应用于骨缺损、修复、损伤或手术部位可包括任何合适的手段,比如直接手术植入、注射或补充其他以提高移植物和宿主组织活力两者的常用手术植入物、支架或注射、植入物的涂覆、手术部位中组织和骨的涂覆或浸泡或喷涂。在一个实施方案中,可采用物理方法,包括但不限于电穿孔、声致穿孔、磁力穿孔、超声或针头注射,以将营养补充材料和/或废物递送材料和递送媒介物或包封于颗粒中的材料或具有材料和递送媒介物的复合物的支架引入到选定的骨缺损、损伤或修复部位。
“包封效率”(EE)定义为在制造期间成功地捕获于微粒中的目的物质的分数。作为一个实例,PLGA微粒的预期EE可能是可变的,并且高度依赖于制造方法和包封剂的类型,但根据采用PLGA微球的现有文献通常落在30-90%范围内。参见例如Han FY,Thurecht KJ,Whittaker AK,等人2016.Bioerodable PLGA-Based Microparticles for ProducingSustained-Release Drug Formulations and Strategies for Improving DrugLoading.Frontiers in Pharmacol.,7:185,通过参考结合至本文中。根据递送媒介物,配方中含有的活性成分的百分数可以更高,比如在单独使用组合物的情况下,或者更低,比如在其中大部分天然植入物本身没有营养或废物清除功能的涂层中。
在任何情况下,配方和递送媒介物的组合应确保在合理体积内具有足够的营养递送和废物清除能力,以在单次给予组合物中维持组织活力和愈合至少1小时-长达4周的时间段。通过重复提供相同或另一种组合物可实现超过4周的持续期望效果,治疗的总持续时间由治疗领域的技术人员确定。
D.组织缺损、手术、修复、伤口或疾病的部位
需要促进组织愈合的“部位”可为包含损伤、受损、侵蚀、脆性或以某种其他方式缺损性的组织的任何数量的区域,使得其受益于促进该部位的细胞刺激和生长。与在不受本发明影响的患者中所见的组织愈合速率相比较,促进细胞刺激和生长旨在导致加速该部位的组织愈合。因此,部位可为骨或其他组织损伤的部位。或者,部位可为手术干预的部位。术语“损伤部位”包括骨的骨折或者软组织或器官创伤的部位。“手术干预部位”意指部位可为手术修复部位,包括制造手术切口或者重新探查现有切口或开放性伤口,以及包括进一步干预比如将植入物插入到骨中。部位也可为损伤部位和手术干预部位两者的组合。换言之,当部位为损伤和手术干预两者之一时,这可为例如将植入物置于骨折部位。另一个实施方案为经皮干预的部位,其不一定涉及制造手术切口或者重新探查现有切口或开放性伤口,而是依赖于使用针头和其他微创手段来注射和以其他方式操纵组织以改善组织愈合。落在本发明预期范围内的这种部位的备选实施方案为本领域技术人员立即显而易见的。
部位可为需要骨融合或者包含受损骨、侵蚀骨或骨缺损的部位。这种实施方案也可彼此组合或者与损伤或手术干预部位组合。其中存在受损和/或侵蚀骨的部位可能更易于损伤,比如,病症比如骨质疏松症患者经历的脆性骨折。进一步地,在其中部位需要骨融合的患者中,可预期该部位也可为损伤部位,其损伤可导致需要骨的融合。例如,脊椎损伤可需要两个椎骨的融合来稳定脊椎。或者,其可为其他病理学的部位,例如由于椎骨之间的变性或畸形所致导致部位通过椎骨的手术融合进行治疗。
术语“包含组织缺损的部位”是指与健康组织相比较具有缺损性组成或结构的该部位组织。这种缺损可为先天性的,或者其可通过损伤、手术或疾病或如本领域技术人员众所周知的其他情况获得。如本领域技术人员意识到的,具有“组织缺损”或受损组织的部位可例如通过放射照相(例如通过X射线或通过计算机断层扫描)或者直接通过手术暴露和可视化进行评价。因此,在本发明的一个优选实施方案中,部位可为相邻脊椎之间的解剖间隙,需要骨移植或植入物来填充骨缺损以实现脊椎融合。认为本发明在其中骨膜剥离显著和电烙术广泛使用通常会产生不佳生物学部位的脊椎融合中特别有用。
本发明还认为可用于修复不太严重受损的组织,从而允许在发生损伤或手术干预之前存在于该部位的组织层得到补充。认为这种实施方案在将植入物插入到骨中之后特别有用,其中认为新骨形成使得植入物可比在不存在本发明效果的情况下更安全地粘附。一个实例包括可用于许多关节置换植入物上的骨向内生长到设计的向内生长表面中。
本发明可允许调节骨愈合以加速以及提高愈合的质量。这将允许更快的愈合和改善骨折或植入固定的巩固。在临床情况下,在骨折愈合/巩固和植入失败之间存在竞争,尤其是在受损骨,例如脆性、病理性或非典型骨折或骨折不愈合的情况下。认为本发明可促进愈合和巩固,从而减少骨折或植入部位的并发症并允许患者更快速地活动。
在本发明任何方面的一个实施方案中,手术干预可为截骨术。“截骨术”包括任何其中有意切割骨以改变其长度、对齐方式、旋转或位置的手术程序。本发明旨在提供一种手段,借以可在这种程序之后加速愈合过程。
在某些手术程序中,骨移植物用于加速骨的生长和愈合。除骨移植物之外,伴随应用本发明,设想可进一步加速骨愈合过程。可使用骨移植物的一个实例包括需要骨融合的情况。认为本发明不仅助于加速移植骨部位的愈合,而且助于愈合其中切除供体骨的部位。因此,在一个实施方案中,手术干预可为从供骨部位移除骨用于骨移植物。在另一实施方案中,手术干预的部位可为骨移植物本身的部位。认为促进骨形成将助于修复骨折部位的骨和/或加速骨形成。促进固定也可用于骨集成(osteointegrated)植入物,例如牙齿、手指、面部假体和听力装置中。
E.通用组成部分
如本文使用的“患者”或“受试者”或“个体”意指哺乳动物,包括人类、兽医或农场动物、家养动物或宠物,以及通常用于临床研究的动物。在一个实施方案中,这些方法和组合物的受试者为人类。在一个实施方案中,受试者具有组织损伤、组织修复或组织疾病。
“药学上可接受的赋形剂或载体”非限制性地是指本发明的活性剂与其一起给予的稀释剂、辅助剂、赋形剂、助剂或媒介物。药学上可接受的载体为由联邦或州政府监管机构批准,或者在美国药典或其他普遍公认的药典中列出的用于动物,并且更特别地用于人类的那些,可为无菌液体,比如水和油,包括石油、动物、植物或合成来源的那些,比如花生油、大豆油、矿物油、芝麻油等。优选地采用水或盐水溶液以及右旋糖和甘油水溶液作为载体,特别是用于注射溶液。合适的药物载体在E.W.Martin的“Remington’s PharmaceuticalSciences”(Mack Publishing Co.,Easton,PA);Gennaro,A.R.,Remington:The Scienceand Practice of Pharmacy,(Lippincott,Williams and Wilkins);Liberman,等人,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.;和Kibbe,等人,Eds.,Handbook of Pharmaceutical Excipients,American PharmaceuticalAssociation,Washington中描述。
如本文使用的术语“治疗”是指赋予受试者益处的任何使用方法,即可缓解、延迟发作、降低严重程度或发病率,或预防如本文先前描述的组织损伤、组织修复或组织疾病的一个或多个症状或方面。为本发明的目的,可在手术治疗之前、期间和/或之后给予治疗。在某些实施方案中,在受试者接受手术之后进行治疗。在一些实施方案中,术语“治疗”包括消除、基本上防止病症的临床或美学症状的出现,或者降低由组织损伤、手术、修复或疾病引起的一种或多种症状的严重程度和/或频率。
“有效量”意指足以在合适的给予过程之后提供治疗益处或治疗效果的营养补充材料和/或废物清除材料或任何任选组成的量。化合物或药物组合物的“治疗有效量”是指对可定量预防、抑制、治疗或减轻特定障碍或疾病的症状有效的量。例如,“治疗有效量”可指足以在经治疗受试者的手术部位刺激细胞或组织修复的,比在手术期间未接受治疗的类似受试者更快或更有效的营养补充材料的量。应当理解的是,营养材料的“有效量”取决于选择用于方法中的材料而变化,以及组织损伤、伤口或疾病的严重程度和程度而变化。应当理解的是,废物清除材料的“有效量”取决于选择用于方法中的材料而变化。关于剂量,应当理解的是,根据其定义的必需营养材料在大剂量范围内为安全的,如本领域对单个营养物已知的。由于本发明不涉及全身生物体,而是仅涉及局部或区域组织损伤,因此剂量通常不由体重决定。对于可注射剂,医师或护士可通过从小瓶中以该量填充注射器来注射计算量。相比之下,植入物或支架可含有固定剂型。小分子的一些剂量范围研究使用mg/kg,但基于本说明书的讲授,本领域的技术人员可使用其他剂量。在一个实施方案中,作为微粒或植入物递送的营养组合物的有效量非限制性地包括约0.001-约500mg/kg受试者体重。在另一个实施方案中,受试者可在手术期间注射有在递送媒介物中的100微克-50克,并且在手术完成之后,可以1-20毫升或5-10cc的体积重复局部注射。
术语“一(a)”或“一(an)”是指一种或多种。例如,“一种氨基酸”可理解为代表一种或多种这种氨基酸。因此,术语“一(a)”(或“一(an)”)、“一种或多种”和“至少一种”在本文中可互换使用。
如本文使用的,除非另外规定,否则术语“约”意指从给定参考加或减10%的可变性。
词语“包含(comprise)”、“包含(comprises)”和“包含(comprising)”应包含地而非排他地解释,即包含其他未规定的组分或工艺步骤。词语“由……组成(consist)”、“由……组成(consisting)”及其变体应排他地而非包含地解释,即排除未具体列举的组分或步骤。
本文中使用的技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同含义,并且参考已发表的文本,其为本领域的技术人员提供本申请中使用的许多术语的一般指南。本说明书中含有的定义是为清楚地描述本文的组分和组合物而提供,并且不旨在限制要求保护的发明。
II.组合物
因此,在一个实施方案中,用于增加组织损伤或伤口部位愈合的组合物,在适合于递送至组织缺损、组织损伤、组织疾病或手术部位的生理学上可接受的递送系统中包含有效量的营养支持材料和任选有效量的废物清除材料。组合物可配制为适合于相关的损伤或手术干预类型。适当的配方为本领域技术人员显而易见的,并且可包括但不限于包含用于植入的固体、用于注射的液体、粉末、片状物、颗粒、微粒、纳米颗粒、胶囊、乳膏、凝胶、乳液、糊状物、涂层、现有植入物或组织的浸渍、其组合。配方可方便地以单位剂型呈现,并且可通过药学领域众所周知的任何方法制备。这种方法包括将活性成分(本发明的配方)与如上所述的合适的递送媒介物缔合的步骤。通常,通过将活性营养成分(和其他废物清除成分)与液体载体或精细粉碎的固体载体或两者均匀和紧密地缔合来制备配方,并然后对产物成型(如果必要的话)。
配方可包括一种控释制剂,其为生物相容性的,在低温下为液体,因此适合于注射,但在体温下呈现凝胶特性。“低温”包括低于典型健康体温的温度含义。这种配方的实例包括基于Pluronic凝胶(Fl 27)和ReGelTM的那些,如本领域技术人员众所周知的。PluronicF127可与交联的聚乙二醇-纤维蛋白原缀合物组合,并将与这些基质组合的营养材料/废物清除材料最佳地递送至期望的活性部位。
当将本发明的组合物引入到合适的递送媒介物中时,用于在其中需要组织愈合或形成的部位局部给予。它们可以无菌水溶液的形式使用,无菌水溶液可含有其他物质,例如足够的盐或葡萄糖以使溶液与血液等渗。如果必要的话,水溶液应适当地缓冲(优选地至pH为3-9)。在一个实施方案中,配方的pH为约7.4,用于应用于组织损伤部位/手术部位。在无菌条件下制备合适的配方易于通过本领域技术人员众所周知的标准药物技术来实现。
适合于局部给予的配方包括水性和非水性无菌注射溶液剂,其可含有抗氧化剂、缓冲剂、抗生素、抗真菌药、抗寄生虫药和使配方与预期受者组织等渗、在免疫学上可接受并预防感染的其他溶质;以及水性和非水性无菌悬浮液,其可包括助悬剂和增稠剂。配方可以单位剂量或多剂量微粒等分试样呈现,并且可在冷冻干燥(冻干)条件下储存,仅需要在使用之前立即添加无菌液体载体,例如用于注射或植入的生理盐水。临时注射溶液剂和悬浮液可由先前描述种类的无菌粉末、颗粒和片剂制备。参见例如US2014/0056960。然后将这些配方制备为微粒、凝胶或在如本文公开的其他递送系统中。
在仍然另一个实施方案中,用于植入到手术部位中的组合物用营养支持材料或废物清除材料涂覆、混合或填充,以在植入到组织缺损或损伤部位中之后逐渐释放。
III.方法
本发明提供一种增加组织损伤或伤口愈合的方法,包括在组织修复部位、组织手术部位或伤口处引入营养支持材料,以提高细胞在伤口环境中的存活率。在一个实施方案中,在组织修复或伤口的所述部位闭合之前,在手术程序期间引入材料。在另一个实施方案中,在手术程序之前或不需要手术程序的情况下将材料引入到组织修复或伤口的部位。在仍然另一个实施方案中,继手术程序之后在所述组织修复或伤口部位闭合之后,将材料引入到组织修复或伤口部位。
如上所述,“材料”可包括本文所述的任何营养支持材料,包括糖、氨基酸、维生素、脂肪酸、矿物质、盐和核酸中的一种或多种和/或细胞培养基。材料应保持生理pH。在另一个实施方案中,方法进一步包括在组织修复或伤口部位引入废物清除材料,以隔离可能对组织愈合或细胞存活产生负面影响的毒素。废物清除材料如上所述,并且在一个实施方案中可包括活性炭。在另一个实施方案中,以纤维素涂覆活性炭。在另一个实施方案中,包括一种或多种类黄酮化合物作为废物清除材料。
在一个实施方案中,营养支持材料包含在递送组合物中,任选地与废物清除材料一起。在一个备选实施方案中,营养支持材料包含在一种配方或递送媒介物中,并且废物清除材料包含于单独的递送媒介物中。对于用于递送至组织的两种类型组合物,这种递送媒介物可为相同或不同的。这种递送媒介物如上所述,并且包括用于植入的固体、用于注射的液体、粉末、片状物、颗粒、微粒、纳米颗粒、胶囊、乳膏、凝胶、乳液、糊状物、涂层、现有植入物或组织的浸渍、其组合或任何生物学上可接受的递送装置。在一个具体实施方案中,递送媒介物为由聚合物比如PLGA组成的微粒。可使用以上提及的仍然其他媒介物。
根据一个实施方案,方法包括用有效量的营养支持材料对组织损伤或伤口部位进行浸泡、涂覆、分层、注射或喷涂,并以相同方式施加任选的废物清除材料。这种施加的部位可为手术区域,包括组织缺损部位和相关组织类型,包括但不限于骨、骨膜、肌肉、肌腱、韧带、软骨、筋膜、脉管系统、肉芽组织、脂肪和真皮。在另一个实施方案中,通过在手术闭合之前于骨损伤或伤口部位插入递送媒介物比如本文所述的那些来引入组合物。在一个实施方案中,递送媒介物能够在损伤或修复或再生部位体内递送有效量的所述营养支持材料和任选的废物清除材料。
在仍然另一个实施方案中,方法包括将能够体内递送有效量的支持材料和任选的废物清除材料的所述营养或废物清除组合物注射到组织损伤或伤口部位。组合物可包括可以该方式递送的液体、凝胶、悬浮液或基质。在另一个实施方案中,组合物的注射可在手术闭合后进行,时间和剂量由外科医生和医师选择。在一个实施方案中,注射在骨损伤或伤口部位的手术闭合之后进行。
方法可在任何合适的手术程序之前、期间、一起或之后应用,比如骨移植、组织修复、脊椎融合或将植入物插入到骨缺损中,以及本文所确定的其它方法。
在局部给予的情况下,给予到配方可改善组织愈合的任何组织腔室内。这可通过同样的另外干预来补充。也就是说,该步骤可以使得在手术期间将植入物或其他递送媒介物局部给予到需要组织活力支持的区域,并然后在术后进行定向注射或者给予到损伤或手术修复部位。在仍然其他实施方案中,营养和/或废物清除材料可与骨移植材料混合并递送。
基于本文提供的教导,组合物和方法的其他实施方案认为在本领域技术范围内。
IV.实施例
以下实施例公开了上述方法和组合物的具体实施方案,并且应当解释为包括由于本文提供的教导而变得显而易见的任何和所有变化。在这些实施例中,Dulbecco改良Eagle培养基(DMEM)为一种富集的细胞培养基。PLGA与DMEM一起提供一种用于生产营养微粒的成分的可靠实例。
实施例1.用于维持细胞活力的营养洗脱和废物清除微粒的开发.
如下所述,我们开发了一种用于产生营养洗脱微粒的方法。作为基线表征的一部分进行微粒表征,包括包封效率(EE)的测量、洗脱特性和显微镜分析。炭基废物清除微粒可任选地与营养物提供协同使用以提高细胞寿命。
A.负载PLGA的营养微粒的制备:使用一种水包油包固体方法。简言之,初级乳液使营养固体均匀地悬浮于溶解聚合物的浴中。在将初级乳液直接添加到表面活性剂(例如PVA;聚乙烯醇)中后,在存在表面活性剂的情况下,由初级乳液与水浴的亲水-疏水相互作用产生尺寸和形状大致均匀的球形液滴。这种称为次级乳液的最终混合物不仅允许形成微粒,而且通过从液滴中逐渐提取有机溶剂来触发颗粒硬化。最终,PLGA颗粒保留在漂浮的表面活性剂溶液中并可通过重力分离去除。
图1A-1C显示用暗场显微镜分析的逐步制造方案的一个实例。氯仿用于初级乳液,而0.5%PVA用作次级乳液的表面活性剂。在室温下,于化学通风橱下将精细DMEM粉末悬浮于含有相等重量溶解PLGA的10x w/v氯仿中,然后进行10秒的浴式超声处理。这就形成了油包固体初级乳液。
在中速涡旋下,将初级乳液滴加到在去离子水中含有过量1%w/v聚乙烯醇的试管中。然后将该水包油包固体次级乳液在磁力搅拌器中以200rpm轻轻搅拌3小时直至微粒充分硬化。倾析过量的上清液,并将剩余微粒转移至小玻璃闪烁瓶中且用冰冷的去离子水洗涤3次,使得颗粒在其间沉降。在1000g下离心5分钟后弃去最终洗涤液。在-80℃下储存微粒直至冻干以产生最终微粒。
B.炭微粒的制备:使用纤维素涂覆的活性炭产生废物清除微粒。按照Park TJ,等人2008.Heparin-cellulose-charcoal composites for drug detoxification preparedusing room temperature ionic liquids.Chem.Commun.:5022-5024发表的方案,采用1-丁基-3-甲基咪唑鎓氯化物([BmIm][Cl])作为初级乳化中的溶剂,使用水包离子液体包固体方法产生纤维素涂覆的炭微粒。将纤维素加入到[BmIm][Cl]中并加热至70℃持续30分钟以完全溶解。将50-150μm尺寸的未涂覆活性炭珠粒在该溶液中搅拌并将该初级乳液滴加到乙醇浴中且搅拌24小时。将珠粒用双蒸馏水洗涤3小时并在干燥器中干燥且以无水分方式储存。
C.营养微粒表征:使用描述的方案可靠地产生直径为50-300微米的微粒。暗场显微术用于在制造后立即确定微粒的尺寸以确保生产一致性(图1A-1C)。
D.包封效率(EE):EE通过对预先称重量的营养微粒进行化学提取来测量,将颗粒溶解于氯仿中然后用去离子水剧烈提取。DMEM含量的测量通过吸光分光光度法进行,使用酚红(DMEM培养基的一种成分)作为DMEM含量指标。在烷化作用之后,使用浓氢氧化钠在560nm处进行测量峰值吸光度。23使用已知浓度的水中DMEM的连续稀释液作为标准,并根据该参考计算EE。
实施例2:微粒在体外维持细胞活力并保持其再生表型.
需要活力测定来证实这些微粒充分支持细胞活力并能够保持干细胞的多能性。使用人类间充质干细胞系可证实营养洗脱微粒或废物清除微粒(或两者)在体外维持细胞活力方面的充分性。为证实再生表型的维持,可评估存活细胞随着时间的推移分化成成骨、软骨和成脂途径的能力。
为此,采用人类间充质干细胞系的共培养实验用于证实微粒保持和维持细胞活力长达21天的能力。然后细胞以时间点间隔经受多能性评价,以证实多能性的持久性。共培养测定的成功表明营养和/或废物清除微粒在保持其再生表型和细胞活力方面的充分性。
使用原代人类骨髓间充质干细胞(hBM-MSC)培养物进行初步细胞活力测定(图2A-2C)。进行活力测定以确定微粒在促进多于一种细胞类型中的细胞活力方面的功效。hMSC细胞系具有能够以各种时间间隔收获细胞以评价其多能表型的维持的另外益处。将细胞置于单独的1x HEPES缓冲盐水(HBSS)或1x HBSS+微粒中,比率为0.65mg微粒/1000个细胞。培养物用台盼蓝溶液染色以在长达60小时的多个时间点进行活力计算。在这两种条件之间细胞活力遇到显著差异。该测定证实了营养对hBM-MSC活力的必要性。
实施例3:蜡涂覆缓慢洗脱营养颗粒
使用DMEM基营养组合物,使用含有95%-100%巴西棕榈蜡的干式涂覆方法产生微粒,以获得固体核心缓慢洗脱营养微粒。固体DMEM颗粒首先用添加小剂量的青霉素、链霉素和两性霉素的抗生素-抗真菌药混合物来抑制不必要的细菌生长来产生。这通过将固体DMEM颗粒相对于巴西棕榈蜡粉末剧烈机械搅动直至颗粒完全涂覆来进行,伴随使用或不使用称重的珠粒作为机械催化剂。
为证实长达4周的细胞活力,将20,000个细胞的等分试样与营养微球、生物相容性炭颗粒或两者的组合,加入到12孔培养板的单独孔中(图3)。将微粒与细胞的比率滴定至每1000个细胞0.5、2和5mg以优化微粒浓度。培养基为含有或不含胎牛血清(ThermoFisher,Waltham,MA)的HEPES缓冲盐水,对照孔含有仅含空白PLGA颗粒的培养基。在0、8和24小时并然后每隔几天收获一式三份直至第25天,以确定细胞活力和增殖的趋势。使用具有Transwell插入物(Corning,Corning,NY)的组织培养板在5%CO2中进行共培养实验,以提供微粒与细胞培养单层的分离。这允许在没有来自微粒的光干扰的情况下易于进行单层成像。
使用该方法产生的微粒的营养洗脱显示出对数分布,半衰期为约20小时并具有合乎期望的早期爆裂释放(图5)。
使用这些蜡涂覆的微粒,使用单层人类骨髓来源的间充质干细胞作为模型细胞类型进行体外活力研究。将细胞与或不与营养微粒一起在盐水中共培养。使用盐水中的2%和10%胎牛血清(FBS)提供阳性对照。还测试了营养微粒加1%血清的协同作用。超过3周的细胞培养活力测试证实了对单独的营养微粒具有强的活力反应,以及不仅对添加剂,而且当与仅1%的血清一起使用时还有协同作用(图6)。当与活性炭微粒一起使用时证实了另外的协同作用,表明废物清除对提高细胞活力的作用(图7)。为确保没有表型损失,对存活3周细胞的多能活性进行了确认(图8)。总体结果表明,营养微粒在体内具有良好作用,其中它们将与细胞外液(含有天然血清的类似营养成分)协同作用以提供细胞维持支持。
为测试这些蜡涂覆的营养微粒在维持组织存活方面的体内功效,进行了一项临床模拟动物研究。在大鼠腰椎融合模型中,使用营养微粒来测试其维持骨移植存活的能力。在该模型中,从经受手术的动物骨盆中采集自体髂骨移植物。将这种骨移植物与空白微粒(仅含蜡;对照组)或等量蜡涂覆的营养微粒(实验组)混合。然后通过暴露L4和L5级腰椎的横突,对宿主骨表面去毛刺并将微粒-骨移植物混合物置入到该宿主部位中,进行腰椎融合。通过X射线分析比较放射照相愈合。该分析的结果证实,营养微粒取代动物中的骨产生与对照相比较明显增加(图9)。
这些实例实验证实了发明人的假设,即补充保持新鲜手术部位中细胞稳态所需的基本因子可提高移植物活力,且从而提高组织愈合率。具体地讲,在骨破坏之后形成柔软的愈合组织之前,移植物在局部组织炎症中浸泡的同时会与可靠的内在血液供应分离一段时间。7因此,补充营养和隔离细胞废物,比如呈局部补充的微粒形式,在其他方面不利的宿主环境中延长细胞活力。
每一项专利、专利申请和出版物,包括整个说明书中引用的网站,均通过参考结合至本文中。尽管已经参考特定实施方案描述了本发明,但是应当意识到,可进行修改而不背离本发明的精神。这种修改旨在落在所附权利要求的范围内。
具体实施方案
1.用于补充组织存活的营养支持材料,其包含
a)用于控制营养物释放的缓慢洗脱载体;和
b)包含葡萄糖的营养混合物;
且其中缓慢洗脱载体的释放半衰期在30分钟-14天之间。
2.实施方案1的营养支持材料,其中营养支持材料为可植入或可注射的。
3.实施方案1或实施方案2的营养支持材料,其中营养混合物包含DMEM、EMEM、RPMI、IMDM、Ham’s F10或Ham’s F12培养基粉末。
4.实施方案1-3中任何一项的营养支持材料,其中材料呈直径在1微米-5mm之间的微粒形式。
5.实施方案1-4中任何一项的营养支持材料,其中载体为载体聚合物基质,任选地为PLGA。
6.实施方案1-3中任何一项的营养支持材料,其中载体为涂层。
7.实施方案6的营养支持材料,其中涂层包含至少95%的蜡或蜡样物质。
8.实施方案1-7中任何一项的营养支持材料,其中材料呈浸渍到多孔植入物中的形式。
9.实施方案1-7中任何一项的营养支持材料,其中材料呈尺寸在2cm-20cm之间的片状物、球体或块形式。
10.实施方案1-7中任何一项的营养支持材料,其中材料呈5纳米-1微米之间的纳米颗粒形式。
11.实施方案1-10中任何一项的营养支持材料,其进一步包含抗生素和/或抗真菌药以抑制不合期望的污染生长。
12.补充与损伤、疾病或手术相关的组织存活的方法,其包括将实施方案1-11中任何一项的营养支持材料给予组织损伤、疾病、手术或伤口部位。
13.补充自体移植骨片的方法,方法包括将实施方案1-11中任何一项的营养支持材料与骨移植物一起给予。
13.补充细胞疗法的方法,方法包括将实施方案1-11中任何一项的营养支持材料与细胞疗法一起给予。
14.增加组织损伤、疾病、手术或伤口愈合的方法,其包括在组织损伤、疾病、手术或伤口部位引入实施方案1-11中任何一项的营养支持材料以提高细胞在伤口环境中的存活率。
15.实施方案14的方法,其中所述材料在所述组织损伤、疾病、手术或伤口部位闭合之前的手术程序期间引入。
16.实施方案14的方法,其中所述材料在手术程序之前引入到组织损伤、疾病、手术或伤口部位。
17.实施方案14的方法,其中所述材料继手术程序之后在所述组织损伤、疾病、手术或伤口部位闭合之后引入到组织损伤、疾病、手术或伤口部位。
18.实施方案14的方法,其中所述材料在没有手术干预的情况下引入到组织损伤或伤口部位。
19.实施方案14-18中任何一项的方法,其中营养支持材料包含糖、氨基酸、维生素、脂肪酸、矿物质、盐和核酸中的一种或多种及细胞培养基的混合物并具有生理pH。
20.实施方案14-19中任何一项的方法,其中所述方法进一步包括在组织损伤、疾病、手术或伤口部位引入废物清除材料,以从组织损伤、疾病、手术或伤口部位去除毒素。
21.实施方案20的方法,其中废物清除材料包含活性炭。
22.实施方案14-21中任何一项的方法,其中所述营养支持材料任选地与所述废物清除材料一起包含在递送组合物中。
23.实施方案22的方法,其中所述递送组合物为用于植入的固体、用于注射的液体、粉末、片状物、颗粒、微粒、纳米颗粒、胶囊、乳膏、凝胶、乳液、糊状物、涂层、现有植入物或组织的浸渍、其组合,或任何生物学上可接受的递送装置。
24.实施方案23的方法,其中所述微粒由PLGA或其他包封聚合物中的一种或多种组成。
25.实施方案14-24中任何一项的方法,其中所述引入步骤包括用有效量的所述支持材料与任选的废物清除材料对组织损伤、疾病、手术或伤口部位进行浸泡、涂覆、分层、注射、浸渍或喷涂中的一种或多种。
26.实施方案14-24中任何一项的方法,其中所述引入步骤包括在手术闭合之前于组织损伤、疾病、手术或伤口部位插入能够在体内递送有效量的所述支持材料和任选的废物清除材料的递送组合物。
27.实施方案14-24中任何一项的方法,其中所述引入步骤包括将能够在体内递送有效量的所述支持材料和任选的废物清除材料的递送组合物注射到组织损伤、疾病、手术或伤口部位中。
28.实施方案24的方法,其中所述注射在所述组织损伤或伤口部位的手术闭合之前、期间或之后进行或在没有手术干预的情况下进行。
29.实施方案14-25中任何一项的方法,其中手术程序为骨移植、组织修复、脊椎融合或将植入物插入到骨缺损中。
30.用于在组织损伤、疾病、手术或伤口部位增加愈合的组合物,其在生理学上可接受的递送系统中包含有效量的营养支持材料和任选有效量的废物清除材料。
31.用于植入到组织损伤、疾病、手术或伤口部位的组合物,其涂覆有营养支持材料或废物清除材料。
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Claims (31)
1.用于补充组织存活的营养支持材料,其包含
a)用于控制营养物释放的缓慢洗脱载体;和
b)包含葡萄糖的营养混合物;
且其中所述缓慢洗脱载体的释放半衰期在30分钟-14天之间。
2.权利要求1的营养支持材料,其中所述营养支持材料为可植入或可注射的。
3.权利要求1或权利要求2的营养支持材料,其中所述营养混合物包含DMEM、EMEM、RPMI、IMDM、Ham’s F10或Ham’s F12培养基粉末。
4.权利要求1-3中任何一项的营养支持材料,其中所述材料呈直径在1微米-5mm之间的微粒形式。
5.权利要求1-4中任何一项的营养支持材料,其中所述载体为载体聚合物基质,任选地为PLGA。
6.权利要求1-3中任何一项的营养支持材料,其中所述载体为涂层。
7.权利要求6的营养支持材料,其中所述涂层包含至少95%的蜡或蜡样物质。
8.权利要求1-7中任何一项的营养支持材料,其中所述材料呈浸渍到多孔植入物中的形式。
9.权利要求1-7中任何一项的营养支持材料,其中所述材料呈尺寸在2cm-20cm之间的片状物、球体或块形式。
10.权利要求1-7中任何一项的营养支持材料,其中所述材料呈5纳米-1微米之间的纳米颗粒形式。
11.权利要求1-10中任何一项的营养支持材料,其进一步包含抗生素和/或抗真菌药以抑制不合期望的污染生长。
12.补充与损伤、疾病或手术相关的组织存活的方法,其包括将权利要求1-11中任何一项的营养支持材料给予所述组织损伤、疾病、手术或伤口部位。
13.补充自体移植骨片的方法,所述方法包括将权利要求1-11中任何一项的营养支持材料与骨移植物一起给予。
13.补充细胞疗法的方法,所述方法包括将权利要求1-11中任何一项的营养支持材料与细胞疗法一起给予。
14.增加组织损伤、疾病、手术或伤口愈合的方法,其包括在所述组织损伤、疾病、手术或伤口部位引入权利要求1-11中任何一项的营养支持材料以提高细胞在所述伤口环境中的存活率。
15.权利要求14的方法,其中所述材料在所述组织损伤、疾病、手术或伤口部位闭合之前的手术程序期间引入。
16.权利要求14的方法,其中所述材料在手术程序之前引入到所述组织损伤、疾病、手术或伤口部位。
17.权利要求14的方法,其中所述材料继手术程序之后在所述组织损伤、疾病、手术或伤口部位闭合之后引入到所述组织损伤、疾病、手术或伤口部位。
18.权利要求14的方法,其中所述材料在没有手术干预的情况下引入到所述组织损伤或伤口部位。
19.权利要求14-18中任何一项的方法,其中所述营养支持材料包含糖、氨基酸、维生素、脂肪酸、矿物质、盐和核酸中的一种或多种及细胞培养基的混合物并具有生理pH。
20.权利要求14-19中任何一项的方法,其中所述方法进一步包括在所述组织损伤、疾病、手术或伤口部位引入废物清除材料,以从所述组织损伤、疾病、手术或伤口部位去除毒素。
21.权利要求20的方法,其中所述废物清除材料包含活性炭。
22.权利要求14-21中任何一项的方法,其中所述营养支持材料任选地与所述废物清除材料一起包含在递送组合物中。
23.权利要求22的方法,其中所述递送组合物为用于植入的固体、用于注射的液体、粉末、片状物、颗粒、微粒、纳米颗粒、胶囊、乳膏、凝胶、乳液、糊状物、涂层、现有植入物或组织的浸渍、其组合,或任何生物学上可接受的递送装置。
24.权利要求23的方法,其中所述微粒由PLGA或其他包封聚合物中的一种或多种组成。
25.权利要求14-24中任何一项的方法,其中所述引入步骤包括用有效量的所述支持材料与任选的废物清除材料对所述组织损伤、疾病、手术或伤口部位进行浸泡、涂覆、分层、注射、浸渍或喷涂中的一种或多种。
26.权利要求14-24中任何一项的方法,其中所述引入步骤包括在手术闭合之前于所述组织损伤、疾病、手术或伤口部位插入能够在体内递送有效量的所述支持材料和任选的废物清除材料的递送组合物。
27.权利要求14-24中任何一项的方法,其中所述引入步骤包括将能够在体内递送有效量的所述支持材料和任选的废物清除材料的递送组合物注射到所述组织损伤、疾病、手术或伤口部位中。
28.权利要求24的方法,其中所述注射在所述组织损伤或伤口部位的手术闭合之前、期间或之后进行或在没有手术干预的情况下进行。
29.权利要求14-25中任何一项的方法,其中所述手术程序为骨移植、组织修复、脊椎融合或将植入物插入到骨缺损中。
30.用于在所述组织损伤、疾病、手术或伤口部位增加愈合的组合物,其在生理学上可接受的递送系统中包含有效量的营养支持材料和任选有效量的废物清除材料。
31.用于植入到所述组织损伤、疾病、手术或伤口部位的组合物,其涂覆有营养支持材料或废物清除材料。
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