A Novel Self-Renewing Heparin-Binding Anti-microbial Device Surface Coating

新型自我更新肝素结合抗菌装置表面涂层

基本信息

批准号：
8072647
负责人：
DAVID W GRAINGER
金额：
$ 18.28万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072647
关键词：
Achievement Address Adhesions Affinity Amino Acid Motifs Animal Testing Architecture Area Binding Biocompatible Materials Biological Assay Biopolymers Blood Blood Platelets Blood Vessels Blood flow Cardiovascular system Catheterization Catheters Chimera organism Chimeric Proteins Cities Clinical Coagulants Devices Dissociation Escherichia coli Frequencies Gram-Negative Bacteria Harvest Hemodialysis Heparin Heparin Binding Human Resources Implant In Vitro Industry Infection International Liquid substance Longevity Mechanics Medical Device Methods Microbial Biofilms Patients Peptides Performance Pharmacologic Substance Plasma Plasmids Polymers Production Property Proteins Publishing Recombinant Proteins Recombinants Resistance Resolution Scheme Silk Sodium Chloride Solutions Spiders Structure Surface Tertiary Protein Structure Testing Therapeutic Thrombosis Thrombus Translations Vertebral column Whole Blood Work antimicrobial base combinatorial copolymer cost density design follow-up improved in vitro activity microbial mimicry natural antimicrobial novel pre-clinical protein expression public health relevance resilience self-renewal shear stress surface coating

项目摘要

DESCRIPTION (provided by applicant): Thrombosis and infection remain long-standing major challenges to the performance and longevity of any blood-contacting medical device. Long-term cardiovascular catheterization, as in the context of hemodialysis and vascular access, presents a significant clinical challenge in this regard. Significantly, thrombus formation and infectious biofilm-based implant infection are frequently inextricably connected, effectively countering resolution with therapeutics, allowing infections and thrombosis to proceed unabated. Many pharmaceutical and materials-based methods addressing biomaterial-associated thrombogenesis have been published. Yet few actively seek combinatorial approaches to address both thrombosis and infection simultaneously while concurrently providing durable mechanical resilience as a biomaterial or coating. These observations frame our overall working hypothesis: a recombinant protein-based polymer containing a cassette for genetically encoding heparin-binding motifs, concatenated with a MaSp2 silk protein backbone, provides a "self- renewing" heparin-enriched polymer material, yielding both hemocompatibility and antimicrobial properties in a surface coating. This biomaterial construct will be based on known recombinant silk-based protein expression, combined with known heparin-binding mimicry for mammalian proteins to yield a new chimera-based biomaterial that actively binds circulating heparin with high affinity. Fabrication of the proposed medical device coating will proceed according to the following specific aims: 1) Determine the critical density of ARKKAAKA that provides both non-thrombogenic and antimicrobial activity in vitro in plasma-based assays.; 2) Determine the critical density of the MaSp2 silk motif, (GGYGPGQQGPGGYGPGQQGPSGPGSAAAAAAAA)n, required to provide a hemodialysis catheter surface coating with appropriate mechanical and antithrombogenic properties under blood flow-induced shear stress; 3) Produce a dual cassette biopolymer-based material combining the heparin-binding peptide (ARKKAAKA)n and the MaSp2 silk motif (GGYGPGQQGPGGYGPGQQGPSGPGSAAAAAAAA)n (where n is determined in Specific Aims 1 and 2), in controlled architectures to provide mechanical integrity, hemocompatibility, and microbial resistance. At the conclusion of this proposal, we will have produced and verified the durability and activity of a novel proteinaceous hemocompatible, antimicrobial, mechanically robust blood-contacting surface coating using a combination of rigorous heparin-binding, antimicrobial, and mechanical integrity assays in either plasma, whole blood or another biologically relevant milieu. PUBLIC HEALTH RELEVANCE: Improved performance for blood-contacting and hemodialysis catheters will benefit millions of patients. The approach described in this proposal will seek to address this need by producing: (1) a new biopolymer biomaterial with versatile control and design features, (2) an intrinsic capability to capture circulating heparins from the host, (3) associated blood-contacting performance benefits from renewable heparinized surfaces, (4) assessment of hemodialysis catheter thrombogenic and antimicrobial properties using industry test standards, and (5) known mass production and cost structures from current silk-based biomaterials efforts. Eventually, rapid translation of the new biomaterial to commercial use as an alternative to the array of heparinized coatings in medical device use currently is desired.

描述（由申请人提供）：血栓形成和感染仍然是对任何接触血液接触医疗装置的性能和寿命的长期主要挑战。在血液透析和血管通道的背景下，长期心血管导管插入术在这方面提出了重大的临床挑战。值得注意的是，血栓形成和传染性生物膜的植入物感染经常是密不可分的，有效地与治疗剂相反，从而使感染和血栓形成不断地进行。许多针对生物材料相关的血栓形成的药物和材料方法已发表。然而，很少有人会积极寻求组合方法来同时解决血栓形成和感染，同时同时提供耐用的机械弹性作为生物材料或涂料。这些观察结果构成了我们的总体工作假设：一种基于重组蛋白的聚合物，该聚合物包含用于遗传编码肝素结合基序的盒，与MASP2丝绸蛋白质链链串联，提供了“自我更新”肝素 - 烯烃 - 烯烃聚合物材料，从而产生了抗抗抗素性的抗抗质体性。这种生物材料构建体将基于已知的重组丝基蛋白表达，并结合已知的肝素结合模仿哺乳动物蛋白，产生一种新的基于Chimera的生物材料，可主动结合具有高亲和力的肝素循环肝素。提议的医疗装置涂料的制造将根据以下特定目的进行：1）确定在基于血浆的测定中同时在体外提供非血清和抗菌活性的Arkkaaka的临界密度。 2）确定MASP2丝基序的临界密度（GGYGPGQQGPGGPGGPGPGQQGPGPGPGPGSAAAAAAAAAAAAAAA），在血液流动诱导的剪切应力下提供适当的机械和抗实用性特性，以提供适当的机械和抗抑制性能的血液透析表面涂层； 3）产生一种双盒生物聚合物的材料，结合肝素结合肽（Arkkaaka）N和MASP2丝图基序（GGYGPGQQGPGGPGGPGPGPGPGPGPGPGPGPGPGPGSAAAAAAAAAAA）N（其中N在特定的目标1和2中确定n可以在1和2中确定n），从而在MICREBSENTICE INSTICANTICE和2中确定了模式的构建机构，并具有控制性的模式。在该提案的结论中，我们将使用严格的肝素结合，抗菌剂和机械完整性分析的组合在血浆中，整个生物或另一种生物乳Milieuu lieuu lieuu lieuue，并结合了严格的肝素结合，抗菌剂和机械完整性分析。公共卫生相关性：提高血液连接和血液透析导管的性能将使数百万患者受益。 The approach described in this proposal will seek to address this need by producing: (1) a new biopolymer biomaterial with versatile control and design features, (2) an intrinsic capability to capture circulating heparins from the host, (3) associated blood-contacting performance benefits from renewable heparinized surfaces, (4) assessment of hemodialysis catheter thrombogenic and antimicrobial properties using industry test standards, and （5）当前基于丝绸的生物材料工作的已知质量生产和成本结构。最终，需要快速将新生物材料转换为商业用途，以替代目前医疗装置中肝素化涂料阵列的替代方法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anti-Coagulant and Antimicrobial Recombinant Heparin-Binding Major Ampullate Spidroin 2 (MaSp2) Silk Protein.

抗凝血和抗菌重组肝素结合大壶腹蛛丝蛋白 2 (MaSp2) 丝蛋白。

DOI：
10.3390/bioengineering9020046
发表时间：
2022-01-19
期刊：
Bioengineering (Basel, Switzerland)
影响因子：
0
作者：
Mulinti P;Diekjürgen D;Kurtzeborn K;Balasubramanian N;Stafslien SJ;Grainger DW;Brooks AE
通讯作者：
Brooks AE

Development and Processing of Novel Heparin Binding Functionalized Modified Spider Silk Coating for Catheter Providing Dual Antimicrobial and Anticoagulant Properties.

新型肝素结合功能化改性蜘蛛丝导管涂层的开发和加工，提供双重抗菌和抗凝特性。

DOI：
10.1016/j.mtla.2020.100937
发表时间：
2020
期刊：
Materialia
影响因子：
3.4
作者：
Mulinti,Pranothi;Kalita,Deep;Hasan,Raquib;Quadir,Mohiuddin;Wang,Yechun;Brooks,Amanda
通讯作者：
Brooks,Amanda