Liver-mimetic device and method for simulation of hepatic function using such device
Inventors
Qu, Xin • GOU, Maling • Zhu, Wei • Chen, Shaochen
Assignees
National Institutes of Health NIH • University of California San Diego UCSD
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Publication Number
US-10954489-B2
Publication Date
2021-03-23
Expiration Date
2034-06-04
Abstract
A liver-mimetic device and method include a 3D polymer scaffold having a matrix of liver-like lobules with hepatic-functioning particles encapsulated within the lobules. In some embodiments, each liver-like lobule is hexagonal in structure and the matrix is in a honeycomb arrangement. In some embodiments, the hepatic-functioning particles are hepatic progenitor cells. In other embodiments, the hepatic-functioning particles are polymer nanoparticles adapted to capture pore-forming toxins.
Core Innovation
The invention provides a liver-mimetic device and method utilizing a three-dimensional (3D) polymer scaffold formed by dynamic optical projection stereolithography (DOPsL) to create a matrix of liver-like lobules encapsulating hepatic-functioning particles. This device closely mimics hepatic micro-architecture and functions by embedding particles capable of performing liver functions, such as hepatic progenitor cells derived from human induced pluripotent stem cells (iPSCs) or polymer nanoparticles adapted to capture pore-forming toxins (PFTs). The 3D scaffold typically comprises hexagonal liver-like lobules arranged in a honeycomb pattern to simulate native liver tissue structure.
The problem addressed includes the significant clinical need for functional liver replacements due to the shortage of donor organs and the limitations of existing preclinical drug testing models. Conventional animal models are unreliable and costly, failing to accurately represent human liver functions because of species-specific differences. Current in vitro liver models and tissue-engineered constructs often lack native liver micro-architecture and feature suboptimal cell sources, such as primary hepatocytes that de-differentiate quickly or tumor-derived cell lines with aberrant function and safety concerns. Furthermore, detoxification of diverse pore-forming toxins remains inadequate with traditional antidotes, and nanoparticle-based intravenous treatments pose risks of secondary poisoning especially in liver failure patients.
This invention overcomes these challenges by enabling rapid, scalable fabrication of 3D liver-mimetic structures with precisely controlled geometry and cellular composition using DOPsL technology. The device's biomimetic scaffold enhances cellular function and organization by replicating the liver's native hexagonal lobule arrangement and allows incorporation of patient-specific iPSC-derived hepatic progenitor cells with supportive cells, facilitating personalized in vitro liver models for drug metabolism studies and disease modeling. Additionally, polymer nanoparticles such as polydiacetylene (PDA) incorporated in the scaffold can attract, capture, and sense PFTs, providing a novel detoxification platform that avoids systemic nanoparticle administration risks.
Claims Coverage
The claims encompass seven main inventive features related to the method and device for simulating hepatic function using bioprinting of 3D liver-like lobule scaffolds encapsulating hepatic-functioning particles.
Method for forming biomimetic 3D polymer scaffold encapsulating hepatic-functioning particles using dynamic optical projection stereolithography
A method involving suspending biological hepatic-functioning particles (such as hepatic progenitor cells derived from human iPSCs) in a prepolymer and photopolymerizing the prepolymer by maskless DOPsL to form a 3D polymer scaffold with a matrix of hexagonal liver-like lobules arranged in honeycomb patterns, encapsulating the particles within the center portions and including channels and central conduits.
Spatial localization of supportive cells to align in channels and conduits for controlled cell-cell interactions
Printing supportive cells such as mesenchymal stem cells and endothelial cells onto the 3D polymer scaffold using DOPsL to spatially localize them to align within channels and central conduits around the hepatic progenitor cells to regulate three-dimensional cell-cell interactions.
Use of patient-specific hepatic progenitor cells derived from human induced pluripotent stem cells
Incorporation of hepatic progenitor cells derived from patient-specific human iPSCs, including those from subjects with liver-affecting diseases, as the biological hepatic-functioning particles encapsulated within the scaffold.
Use of methacrylated hyaluronic acid or gelatin methacrylate as prepolymer
Utilization of biocompatible prepolymers such as methacrylated hyaluronic acid (MeHA) or gelatin methacrylate (GelMA) in forming the 3D polymer scaffold encapsulating hepatic-functioning cells.
Incorporation of polymer nanoparticles such as polydiacetylene tethered to the scaffold
In some embodiments, polymer nanoparticles, specifically polydiacetylene (PDA), are incorporated within the prepolymer and chemically tethered to the 3D polymer scaffold to capture pore-forming toxins within the liver-like lobules.
Simulation of hepatic function including detoxification by exposure to blood or blood cells
Exposing the 3D liver-mimetic scaffold encapsulating hepatic-functioning particles (cells or nanoparticles) to materials such as blood or blood cells to simulate hepatic functions including detoxification.
Co-culture tri-culture system with endothelial cells and mesenchymal stem cells in vascular patterns
Printing of endothelial cells and mesenchymal stem cells into defined vascular-like patterns within the scaffold to support hepatic progenitor cells and mimic liver microvasculature.
The claims collectively cover a method and device for producing a biomimetic 3D polymer scaffold with hexagonal liver-like lobules encapsulating hepatic-functioning particles such as iPSC-derived hepatic progenitor cells and polymer nanoparticles, using dynamic optical projection stereolithography. The claims encompass spatially controlled co-culture with supportive cells, use of patient-specific cell sources, scaffold formation from specific biopolymers, and enabling hepatic functions including detoxification by exposure to biological materials.
Stated Advantages
Rapid, scalable fabrication of highly specified biomimetic liver structures with native hepatic micro-architecture.
Ability to create patient-specific liver-on-a-chip models using hepatic progenitor cells derived from iPSCs to enhance experimental reproducibility and personalized disease modeling.
Improved mimicry of hepatic function by co-culturing hepatic progenitor cells with supportive mesenchymal stem cells and endothelial cells within the scaffold.
Enhanced detoxification capability by incorporating polydiacetylene nanoparticles that attract, capture, and sense pore-forming toxins while avoiding systemic nanoparticle administration risks.
Cost-effective and reliable platform to facilitate drug metabolism studies, preclinical drug screening, and fundamental hepatology research.
Documented Applications
Use as an in vitro platform for drug metabolism studies and preclinical drug screening.
Simulation of hepatic function including detoxification of blood or blood cells.
Creation of personalized in vitro disease models using patient-specific iPSC-derived hepatic progenitor cells for diseases affecting the liver such as cancer and glycogen storage disease type I.
Development of nanoparticle-enabled detoxification devices to neutralize pore-forming toxins in blood.
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