Antifungal Dermal Templates for Wound Healing

用于伤口愈合的抗真菌皮肤模板

基本信息

批准号：
10081001
负责人：
Manav Mehta
金额：
$ 30万
依托单位：
GEL4MED, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-14 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081001
关键词：
Affect Affinity Amputation Animal Model Anti-Bacterial Agents Antibiotic Therapy Antifungal Agents Antimicrobial Resistance Bacteria Bacterial Infections Binding Biomedical Engineering Candida albicans Cell Proliferation Cell-Matrix Junction Clinical Collagen Communities Complex Control Groups Dermal Diabetic mouse Epidemic Epithelial Epithelium Equipment Malfunction Extracellular Matrix Formulation Future Gel Goals Healthcare Histopathology Hydrogels Immune response In Situ In Vitro Infection Knowledge Lead Legal patent Licensing Life Mammalian Cell Membrane Microbial Biofilms Microscopic Mycoses Natural regeneration Optics Pathogenicity Patients Peptide Hydrolases Peptides Phase Prevention Property Public Health Resistance development Shapes Site Skin Substitutes Small Business Innovation Research Grant Sterility Technology Testing Therapeutic Thick Time TimeLine Tissues Topical application United States Validation Work Wound Infection Wound models antimicrobial biomaterial compatibility chronic wound clinically relevant commercialization cost design diabetic patient effective therapy fungus improved in vivo innovation lead candidate manufacturing scale-up mechanical properties microbial multi-drug resistant pathogen neglect non-healing wounds novel pathogen pathogenic bacteria pathogenic fungus phase 2 study pre-clinical prevent regenerative scaffold self assembly standard of care technological innovation tissue regeneration tissue support frame wound wound closure wound dressing wound environment wound healing wound treatment

项目摘要

The goal of this Phase I SBIR is to investigate the antifungal properties of G4Derm against the complex problem of interkingdom polymicrobial infections in non-healing wounds, utilizing a step-wise approach. Problem to be solved and its magnitude. Non-healing wounds pose a great threat to the public health and burden to the economy. In the United States alone, chronic wounds affect 6-8 million patients and result in an excess of >$25 billion annual health care expenses 1,2. The majority of these costs are related to the treatment of infected DFUs 1. The complexity of the polymicrobial wound bioburden, often harboring multi-drug resistant organisms (MDROs), including pathogenic fungi, further contributes to the chronicity of the wounds and recalcitrance to treatment 3–5. Therefore, there is an urgent need for new antimicrobial approaches that present broad-spectrum activity against both bacteria and fungi to effectively treat chronic wounds. Gap in knowledge the technology will fill. In patients with infected chronic wounds, such as DFUs, effective management of wound bioburden is crucial to prevent severe complications including amputation. Fungal infection is a neglected aspect of chronic wound management, and emerging studies have begun to highlight the need to eliminate both bacterial and fungal pathogens 4. Standard of care does not include antifungal treatment, and pathogens are increasingly developing resistance to conventional antifungals, especially in diabetic patients 6–9. Moreover, solely targeting bacteria in mixed communities results in increased fungal diversity and expansion 10. Additionally, while many antimicrobials are available as wound dressing materials targeting bacteria, they can be toxic to tissue regeneration . For example, antimicrobial hydrogels can clear several strains of bacteria but lack the ability to facilitate host cell proliferation . On the contrary, 20–22 23,24,25 bioengineered skin substitutes promote better tissue regeneration but have numerous challenges such as high costs, limited shelf life, difficult administration, uncontrolled degradation in protease-rich wound environments, and most importantly, device failure due to pathogenic colonization 26,27 because several bacterial and fungal pathogens have an affinity for, and bind to collagen 28–30,31 , thus reserving these expensive products until wound sterility is achieved. Therefore, there is an unmet clinical need for an early, safe, and effective treatment of infected chronic wounds (namely DFUs) that eliminates interkingdom polymicrobial infection and, at the same time, induces wound closure and tissue regeneration. Solution: We propose here a novel self-assembling tissue scaffolding matrix, G4Derm, to (i) prevent/eliminate colonization of infectious pathogens through a unique mechanism of action that is broad spectrum antibacterial and antifungal, and (ii) promote wound closure and tissue regeneration by providing cell attachment sites within the scaffolding matrix. Additionally, G4Derm can gel in situ and conforms to unique wound shapes and depths, thereby enabling easy administration. To establish the feasibility, we propose the following specific aims: Specific aim 1) Demonstrate broad-spectrum antifungal capacity in vitro. Milestones: minimum of 4-log CFU reduction by G4Derm (lead candidate) vs. untreated controls against all fungi tested. Specific aim 2) Demonstrate therapeutic in vivo efficacy of G4Derm to eliminate Candida albicans while promoting wound closure in a diabetic mouse full thickness wound model. Milestones: (a) clearing of C. albicans in infected wounds by < 103 CFU/g of tissue quantified by fungal titers at day 1 comparing average CFU/g of wound tissue treated by G4Derm to untreated control group; (b) wound closure in G4Derm-treated groups compared to untreated control by quantitative optical microscopic, and histopathology assessments at day 21. The results from these studies will enable a Phase II proposal to further evaluate G4Derm’s efficacy against mixed bacterial-fungal pathogens, prevention and treatment of biofilms, GLP/ GMP studies for regulatory approvals, and validation in clinically relevant larger animal models of wound healing while eliminating microbial infections.

第一阶段 SBIR 的目标是研究 G4Derm 针对复合物的抗真菌特性不愈合伤口中的跨界多种微生物感染问题，利用逐步方法方法。需要解决的问题及其严重程度对公众健康和健康构成了巨大威胁。仅在美国，慢性伤口就影响着 6-800 万名患者，并导致经济负担。每年医疗保健费用超过 250 亿美元1,2 其中大部分费用与治疗有关。感染 DFU 的原因 1. 多种微生物伤口生物负载的复杂性，通常具有多重耐药性有机体（MDRO），包括致病真菌，进一步导致伤口的慢性化和治疗顽抗 3-5 因此，迫切需要新的抗菌方法。对细菌和真菌具有广谱活性，可有效治疗慢性伤口。该技术将填补慢性伤口感染（例如 DFU）患者的知识空白。伤口生物负载的管理对于预防包括截肢在内的严重并发症至关重要。感染是慢性伤口处理中被忽视的一个方面，新兴的研究已经开始强调需要消除细菌和真菌病原体 4. 标准护理不包括抗真菌药物治疗，病原体越来越多地对传统抗真菌药物产生耐药性，特别是在糖尿病患者 6-9 然而，仅针对混合群落中的细菌会导致真菌增加。多样性和扩展 10. 此外，虽然许多抗菌剂可用作伤口敷料材料针对细菌，它们可能对组织再生有毒，例如，抗菌水凝胶可以清除。相反，一些细菌菌株缺乏促进宿主细胞增殖的能力。 20–22 23,24,25 生物工程皮肤替代品可促进更好的组织再生，但面临许多挑战，例如高成本，有限的保质期，管理困难，富含蛋白酶的伤口环境中不受控制的降解，最重要的是，由于致病菌定植导致设备故障 26,27 因为有多种细菌和真菌病原体对胶原蛋白有亲和力并与其结合 28–30,31 ，从而保留这些昂贵的产品直到上链因此，对早期、安全、有效的治疗的临床需求尚未得到满足。感染的慢性伤口（即 DFU）可消除跨界多种微生物感染，同时时间，诱导伤口闭合和组织再生。解决方案：我们在此提出一种新型自组装组织支架基质 G4Derm，以 (i) 预防/消除通过独特的广谱抗菌作用机制实现传染性病原体的定植和抗真菌，并且（ii）通过提供细胞附着位点促进伤口闭合和组织再生此外，G4Derm 可以在原位凝胶并符合独特的伤口形状和形状。深度，从而使管理变得容易。为了确定可行性，我们提出以下具体目标：具体目标 1) 展示体外广谱抗真菌能力里程碑：最低 4-log CFU。与未经处理的对照相比，G4Derm（主要候选药物）对所有测试真菌的减少量。具体目标 2) 证明 G4Derm 消除白色念珠菌的体内疗效，同时促进糖尿病小鼠全层伤口模型的伤口闭合里程碑：(a) 清除 C. 感染伤口中的白色念珠菌数量 < 103 CFU/g 组织（通过第一天真菌滴度定量，与平均值比较）经 G4Derm 处理的伤口组织与未处理对照组的 CFU/g；(b) G4Derm 处理的伤口闭合；通过定量光学显微镜和组织病理学评估将各组与未治疗的对照组进行比较第 21 天。这些研究的结果将使 II 期提案能够进一步评估 G4Derm 的功效混合细菌-真菌病原体、生物膜的预防和治疗、监管 GLP/ GMP 研究在伤口愈合的临床相关大型动物模型中获得批准和验证，同时消除微生物感染。