Perfusion decellularization and recellularization for the creation of a bioengineered transplantable liver
灌注脱细胞和再细胞化用于创建生物工程可移植肝脏
基本信息
- 批准号:9908268
- 负责人:
- 金额:$ 112.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-17 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAcuteAcute Liver FailureAddressAffectAlbuminsAllogenicAmmoniaAnimal ModelAnimalsAnticoagulant therapyBile AcidsBile Duct EpitheliumBile fluidBiological AssayBiomedical EngineeringBloodBlood VesselsBlood flowCause of DeathCellsChronicClinical ResearchCoculture TechniquesConditioned Culture MediaDataDevelopmentDonor personEndothelial CellsEndotheliumEngraftmentExcisionFamily suidaeGoalsHepatocyteHourHumanImplantIn VitroLegal patentLiverLiver FailureLiver diseasesMeasuresMedicalModelingOrganOrgan ProcurementsPerfusionPhaseProductionRecoveryRecovery of FunctionReportingSeedsSerumSmall Business Innovation Research GrantStructureSurvival RateTechnologyTestingTherapeuticTransplantationUmbilical veinUnited StatesUreaVascular PatencyVery low density lipoproteinbasebile ductcell typecholangiocyteclinically translatablegraft functionin vivoliver functionliver transplantationmeetingsnovel therapeuticsoff-patentreconstitutionscaffoldscreeningtransplant model
项目摘要
ABSTRACT
Liver transplantation currently represents the only treatment for end stage liver disease (ESLD), the 8th most
frequent cause of death in the United States (US). Efforts to overcome the chronic shortage of transplantable
human livers include attempts at alternative organ procurement and replacement strategies. The most promising
approach to date that provides the appropriate matrix composition and supporting vascular structures has been
the development of perfusion decellularization, which enables the removal of cellular material for a native organ
while maintaining the native matrix, structure and vascular of the liver. Utilizing perfusion decellularization and
recellularization technology, several groups have demonstrated the ability to seed a variety of liver-specific cell
types into decellularized liver constructs, however reconstitution of the endothelial cell lining of the vascular
networks in these scaffolds has remained a significant challenge to the development of a therapeutic
bioengineered liver (BEL). Miromatrix Medical Inc. has recently reported revascularizing a clinically translatable
porcine-derived liver scaffold and demonstrated in vivo graft patency in a large animal model without sustained
administration of anticoagulant therapies. Solving the critical vascular constraint allows this Direct to Phase II
SBIR project to focus on production and testing of a fully functional BEL to address the chronic shortage of
transplantable livers and develop new therapeutic options to those with ESLD utilizing Miromatrix’ broad
proprietary perfusion decellularization and recellularization technology.
In Specific Aim #1, we will demonstrate recellularized liver graft function in an acute liver failure model. The
optimal media and seeding conditions for hepatocyte functionality will be selected (1.1). Equivalency of human
hepatocytes to porcine hepatocytes will be demonstrated (1.2), and vascular patency of endothelial and
hepatocyte recellularized livers will be confirmed in acute blood loops (1.3). Forty-eight hour functionality of this
liver graft will be demonstrated in pigs (1.4). In Specific Aim #2, we will optimize the seeding of cholangiocytes
into liver grafts recellularized with endothelial cells and hepatocytes and identify assays that will allow
assessment of cholangiocyte function after seeding to verify successful engraftment (2.1). We will then create
tri-culture grafts using only human cells and test for equivalency to the porcine+human grafts (2.2) and determine
whether addition of cholangiocytes to endothelial+hepatocyte liver grafts adversely affects graft patency (2.3).
Finally, in Specific Aim #3, we will demonstrate the BEL functionality in an orthotopic chronic liver failure model
by developing a transplant model and evaluating baseline data (3.1) and by demonstrating liver functionality for
fourteen days in a recovery model in pigs (3.2). Data generated will be used in a Pre-IND submission meeting
to define the testing required for complete human recellularization and functional testing of the BEL grafts to
initiate clinical studies.
摘要
肝移植目前是终末期肝病(ESLD)的唯一治疗方法,排在第八位
美国(美国)常见的死因。努力克服可移植器官长期短缺的问题
人体肝脏包括替代器官采购和替代策略的尝试。最有希望的
迄今提供适当基质组合物和支持血管结构的方法
灌注脱细胞技术的发展,使天然器官的细胞物质得以去除
同时保持肝脏的天然基质、结构和血管。利用灌流脱细胞和
再细胞化技术,几个小组已经展示了种植各种肝脏特异性细胞的能力
类型进入脱细胞的肝脏结构,然而血管内皮细胞衬里的重建
这些支架中的网络仍然是开发一种治疗性药物的重大挑战
生物工程肝(BEL)。MiroMatrix Medical Inc.最近报告称,重新血管化了一种临床可翻译的
猪源性肝支架在大型动物模型中的体内移植通畅性
抗凝剂治疗的管理。解决关键的血管约束使这一过程直接进入第二阶段
SBIR项目将专注于生产和测试功能齐全的BEL,以解决长期缺乏
利用MiroMatrix公司的BREAD开发可移植肝脏并为ESLD患者开发新的治疗方案
专有的灌流去细胞和再细胞技术。
在具体目标#1中,我们将在急性肝功能衰竭模型中展示再细胞化的肝移植功能。这个
将选择肝细胞功能的最佳培养基和播种条件(1.1)。人类的等价性
肝细胞到猪肝细胞将显示(1.2),血管内皮细胞和血管通畅
肝细胞再细胞化的肝脏将在急性血流循环中被确认(1.3)。这款产品的48小时功能
肝移植将在猪身上进行演示(1.4)。在特定目标#2中,我们将优化胆管细胞的接种
移植到含有内皮细胞和肝细胞的移植物中,并鉴定出将使
种植后评估胆管细胞功能以验证成功植入(2.1)。然后我们将创建
只使用人类细胞的三种培养移植物,测试与猪+人移植物的等效性(2.2),并确定
在内皮细胞+肝细胞肝移植中加入胆管细胞是否会对移植肝的通畅性产生不利影响(2.3)。
最后,在特定的目标#3中,我们将在原位慢性肝衰竭模型中演示BEL的功能
通过开发移植模型和评估基线数据(3.1),并通过展示肝脏功能
在猪的恢复模型中14天(3.2)。生成的数据将用于IND前提交会议
定义完全人类再细胞化所需的测试和BEL移植物的功能测试
启动临床研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jeffrey James Ross其他文献
Jeffrey James Ross的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jeffrey James Ross', 18)}}的其他基金
Perfusion decellularization and recellularization for the creation of a bioengineered transplantable liver
灌注脱细胞和再细胞化用于创建生物工程可移植肝脏
- 批准号:
10018893 - 财政年份:2019
- 资助金额:
$ 112.95万 - 项目类别:
相似海外基金
Senescent hepatocytes mediate reprogramming of immune cells in acute liver failure
衰老肝细胞介导急性肝衰竭中免疫细胞的重编程
- 批准号:
10679938 - 财政年份:2023
- 资助金额:
$ 112.95万 - 项目类别:
Hepatocytes Encapsulated with mesenchymal stromal cells in alginate microbeads for the treatment of acute Liver failure in Paediatric patients (HELP)
将间充质基质细胞封装在藻酸盐微珠中的肝细胞用于治疗儿科患者的急性肝衰竭(HELP)
- 批准号:
MR/V038583/1 - 财政年份:2022
- 资助金额:
$ 112.95万 - 项目类别:
Research Grant
Development of the innovative treatment using self iPS cell for acute liver failure
开发利用自身 iPS 细胞治疗急性肝衰竭的创新疗法
- 批准号:
21K08685 - 财政年份:2021
- 资助金额:
$ 112.95万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pediatric Acute Liver Failure Immune Response Network (PALF IRN): Treatment for Immune Mediated Pathophysiology (TRIUMPH)
小儿急性肝衰竭免疫反应网络 (PALF IRN):免疫介导的病理生理学治疗 (TRIUMPH)
- 批准号:
10421290 - 财政年份:2021
- 资助金额:
$ 112.95万 - 项目类别:
Pediatric Acute Liver Failure Immune Response Network (PALF IRN): Treatment for Immune Mediated Pathophysiology (TRIUMPH)
小儿急性肝衰竭免疫反应网络 (PALF IRN):免疫介导的病理生理学治疗 (TRIUMPH)
- 批准号:
10180251 - 财政年份:2021
- 资助金额:
$ 112.95万 - 项目类别:
Therapeutic effect of plasmacytoid dendritic cells transplantation for acute liver failure
浆细胞样树突状细胞移植治疗急性肝衰竭的疗效
- 批准号:
20K21607 - 财政年份:2020
- 资助金额:
$ 112.95万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Macrophage Therapy for Acute Liver Failure
巨噬细胞治疗急性肝衰竭
- 批准号:
MR/T044802/1 - 财政年份:2020
- 资助金额:
$ 112.95万 - 项目类别:
Research Grant
Investigation of an optimal environment for the proliferation of mature hepatocytes toward the rescue of acute liver failure patients
研究成熟肝细胞增殖的最佳环境以挽救急性肝衰竭患者
- 批准号:
19K08475 - 财政年份:2019
- 资助金额:
$ 112.95万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pediatric Acute Liver Failure (PALF) TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)
小儿急性肝衰竭 (PALF) 免疫介导病理生理学治疗 (TRIUMPH)
- 批准号:
9789253 - 财政年份:2018
- 资助金额:
$ 112.95万 - 项目类别:
Cryopreservation of hiPS-derivd hepatic progenitor cells and application to acute liver failure treatment
hiPS源性肝祖细胞的冷冻保存及其在急性肝衰竭治疗中的应用
- 批准号:
18K08662 - 财政年份:2018
- 资助金额:
$ 112.95万 - 项目类别:
Grant-in-Aid for Scientific Research (C)