Bioresorbable Polythioketal Urethane Wound Dressings

生物可吸收聚硫缩酮聚氨酯伤口敷料

• 批准号: 10734630
• 负责人: Craig Lewis Duvall
• 金额: $ 58.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734630
• 关键词: Acceleration; Address; Admission activity; Animal Model; Becaplermin; Benchmarking; Biocompatible Materials; Biomedical Engineering; Carbon Dioxide; Cattle; Cells; Cellular Infiltration; Cellulose; Cessation of life; Chemistry; Clinical; Collaborations; Collagen; Couples; Crosslinker; Data; Devices; Diabetes Mellitus; Engineering; Equilibrium; Excision; FDA approved; Family suidae; Formulation; Gene Expression; Generations; Glycols; Glycosaminoglycans; Goals; Granulation Tissue; Health Care Costs; Healthcare Systems; Histologic; Histopathology; Hospitals; Hydrolysis; Hydrophobicity; Hydroxyl Radical; Immune; Immunologics; Immunology; Incidence; Infiltration; Ischemia; Isocyanates; Kinetics; Lead; Legal patent; Length; Libraries; Modeling; Morbidity - disease rate; Nature; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathologic; Phenotype; Platelet-Derived Growth Factor; Polyesters; Polymers; Polyurethanes; Porosity; Process; Procollagen-Proline Dioxygenase; Property; Publications; Publishing; Reaction; Reactive Oxygen Species; Recombinants; Series; Side; Silicones; Silver; Site; Skin; Small Interfering RNA; Source; Sterile coverings; Technology; Testing; Time; Tissues; Translational Research; Urethane; Variant; Vertebral column; Water; Work; Wound Infection; Wound models; adaptive immune response; aging population; chronic wound; clinical application; clinical development; clinically relevant; cost; crosslink; density; design; diabetic; diabetic patient; diabetic rat; diabetic ulcer; ethylene glycol; fabrication; healing; hydrophilicity; immunogenic; immunogenicity; in vivo; innovation; invention; lead candidate; limb amputation; manufacture; mechanical properties; multidisciplinary; nanoparticle; next generation; novel; polyurethane foam; pre-clinical; prisma; repaired; response; scaffold; screening; skin wound; success; timeline; tissue repair; translational medicine; wound; wound care; wound dressing; wound healing

PROJECT SUMMARY/ABSTRACT Nonhealing skin wounds are a major source of morbidity worldwide and becoming more of a burden due to an increase in health care costs, an aging population, and growing incidence of diabetes. Non-healing skin wounds occur in nearly 25% of diabetic patients, and ~6% are admitted to the hospital for wound-related treatment, which if not successful, can lead to limb amputation or death. More advanced treatments such as synthetic, resorbable dressings that are placed into the wound to provide a scaffolding for cell infiltration and new tissue formation have started to gain clinical impact. However, currently available polymeric biomaterial wound dressings degrade by hydrolysis, releasing acidic byproducts, creating an autocatalytic degradation process. This can lead to inconsistent degradation rate over time and poor matching between the timeline of cell infiltration / new tissue formation and the timeline of polymeric scaffold resorption. The overall goal of the current project is to develop and apply a next generation cellular reactive oxygen species (ROS) degradable, fully synthetic foam wound dressing. These scaffolds are formed by the reaction of ROS-degradable polythioketal (PTK) diols with isocyanate-containing compounds in the presence of a small quantity of water. This generates a crosslinked polyurethane (resultant bond from reaction of isocyanate and hydroxyl) network that is highly porous in nature due to CO2 generation via the blowing reaction between isocyanates and water. The properties of the resultant polythioketal urethane (PTK-UR) foams can be tuned based on the composition of the PTK diol crosslinker which makes up the bulk of the foam. We propose to develop a library of PTK diols with controlled variation in degree of hydrophilicity, consistent density of thioketal bonds in the backbone, and low potential for immunogenicity. This plan is based on highly- promising preliminary data that PTK-UR scaffold hydrophilicity is a critical factor in the wound healing response to the PTK-UR biomaterials. The proposed polymer series will fill previous gaps in our previous work by yielding a well-controlled, highly-scalable chemistry for better fine tuning of PTK-UR hydrophobic/hydrophilic balance across a broad range with diol chemistries that are not based on potentially immunogenic PEG. The aims of the project will involve synthesis and screening of this new class of thioketal diols, benchmarking of the leading PTK- UR formulations against clinical products for wound healing efficacy, and application of lead PTK-UR formulations for cargo delivery to promote healing in the context of pathological (infected and diabetic) wounds. Our multidisciplinary team includes bioengineers, polymer and polyurethane material chemists, preclinical wound healing model and histopathology expertise, expertise in immunology of wound healing / skin wound infection, and clinical wound care. This group is poised to achieve the proposed goals toward establishing a new clinically impactful, cell-resorbable, synthetic polymer-based foam wound dressing.

项目总结/摘要 不愈合的皮肤伤口是世界范围内发病率的主要来源，并且由于 医疗保健费用的增加、人口老龄化和糖尿病发病率的上升。皮肤不愈合 近25%的糖尿病患者发生伤口，约6%的糖尿病患者因伤口相关原因住院。 治疗，如果不成功，可能导致截肢或死亡。更先进的治疗方法，如 将合成的可吸收敷料置于伤口中，为细胞浸润提供支架， 新的组织形成已经开始获得临床效果。然而，目前可用的聚合物生物材料 伤口敷料通过水解降解，释放酸性副产物，产生自催化降解 过程这可能导致随时间的不一致的降级速率以及小区的时间轴之间的不良匹配 浸润/新组织形成和聚合物支架再吸收的时间轴。 本项目的总体目标是开发和应用下一代细胞活性氧 活性氧（ROS）可降解，全合成泡沫伤口敷料。这些支架是由以下物质的反应形成的： ROS-可降解的聚硫代缩酮（PTK）二醇与含异氰酸酯的化合物在小的 水的数量。这产生交联的聚氨酯（由异氰酸酯和异氰酸酯的反应产生的键）。 羟基）网络，其由于经由发泡反应产生CO2而在性质上是高度多孔的， 异氰酸酯和水。所得聚硫代缩酮聚氨酯（PTK-UR）泡沫的性能可以调节 基于构成泡沫主体的PTK二醇交联剂的组成。 我们建议开发一个PTK二醇库，其亲水性程度可控变化， 骨架中硫代缩酮键的密度和低的免疫原性潜力。这个计划是基于高度- 有希望的初步数据表明，PTK-UR支架亲水性是伤口愈合反应的关键因素 PTK-UR生物材料。拟议的聚合物系列将填补以前的空白，在我们以前的工作， 一种控制良好、高度可扩展的化学品，可更好地微调PTK-UR疏水/亲水平衡 在广泛的范围内使用不基于潜在免疫原性PEG的二醇化学。的目标 该项目将涉及此类新型硫缩酮二醇的合成和筛选，以及领先PTK的基准测试- UR制剂与临床产品的伤口愈合疗效比较，以及PTK-UR先导物的应用 用于货物递送以促进病理性（感染和糖尿病）伤口愈合的制剂。 我们的多学科团队包括生物工程师、聚合物和聚氨酯材料化学家、临床前 伤口愈合模型和组织病理学专业知识，伤口愈合/皮肤伤口免疫学专业知识 感染和临床伤口护理。该小组准备实现拟议的目标， 具有临床影响力、细胞可吸收、合成聚合物基泡沫伤口敷料。

项目成果

MiRNA inhibition in tissue engineering and regenerative medicine.

• DOI: 10.1016/j.addr.2014.12.006
• 发表时间: 2015-07-01
• 期刊: ADVANCED DRUG DELIVERY REVIEWS
• 影响因子: 16.1
• 作者: Beavers, Kelsey R.;Nelson, Christopher E.;Duvall, Craig L.
• 通讯作者: Duvall, Craig L.

Conjugation of palmitic acid improves potency and longevity of siRNA delivered via endosomolytic polymer nanoparticles.

• DOI: 10.1002/jbm.a.35413
• 发表时间: 2015-09
• 期刊: Journal of biomedical materials research. Part A
• 作者: Sarett SM;Kilchrist KV;Miteva M;Duvall CL
• 通讯作者: Duvall CL

Hydrogel microspheres for spatiotemporally controlled delivery of RNA and silencing gene expression within scaffold-free tissue engineered constructs.

• DOI: 10.1016/j.actbio.2021.01.013
• 发表时间: 2021-04-01
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: McMillan A;Nguyen MK;Huynh CT;Sarett SM;Ge P;Chetverikova M;Nguyen K;Grosh D;Duvall CL;Alsberg E
• 通讯作者: Alsberg E

Technologies for controlled, local delivery of siRNA.

• DOI: 10.1016/j.jconrel.2015.09.066
• 发表时间: 2015-11-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Sarett SM;Nelson CE;Duvall CL
• 通讯作者: Duvall CL

Hydrolytic charge-reversal of PEGylated polyplexes enhances intracellular un-packaging and activity of siRNA.

聚乙二醇化复合物的水解电荷反转增强了 siRNA 的细胞内解包装和活性。

• DOI: 10.1002/jbm.a.35629
• 发表时间: 2016
• 期刊: Journal of biomedical materials research. Part A
• 作者: Werfel,ThomasA;Swain,Corban;Nelson,ChristopherE;Kilchrist,KameronV;Evans,BrianC;Miteva,Martina;Duvall,CraigL
• 通讯作者: Duvall,CraigL