title: Towards a Humanized Mouse Model of Liver Stage Malaria Using Ectopic Artificial Livers.
abstract: The malaria liver stage is an attractive target for antimalarial development, and preclinical malaria models are essential for testing such candidates. Given ethical concerns and costs associated with non-human primate models, humanized mouse models containing chimeric human livers offer a valuable alternative as small animal models of liver stage human malaria. The best available human liver chimeric mice rely on cellular transplantation into mice with genetically engineered liver injury, but these systems involve a long and variable humanization process, are expensive, and require the use of breeding-challenged mouse strains which are not widely accessible. We previously incorporated primary human hepatocytes into engineered polyethylene glycol (PEG)-based nanoporous human ectopic artificial livers (HEALs), implanted them in mice without liver injury, and rapidly generated human liver chimeric mice in a reproducible and scalable fashion. By re-designing the PEG scaffold to be macroporous, we demonstrate the facile fabrication of implantable porous HEALs that support liver stage human malaria (P. falciparum) infection in vitro, and also after implantation in mice with normal liver function, 60% of the time. This proof-of-concept study demonstrates the feasibility of applying a tissue engineering strategy towards the development of scalable preclinical models of liver stage malaria infection for future applications.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Shengyong
authors.initials: S
authors.lastname: Ng
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|Broad Institute, Cambridge, MA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: March
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|Broad Institute, Cambridge, MA, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Galstian
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Nil
authors.initials: N
authors.lastname: Gural
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Stevens
authors.affiliation: Unidade de Malária, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|Broad Institute, Cambridge, MA, USA.|Howard Hughes Medical Institute, Koch Institute, and Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D017690:Cell Transplantation / Q000379:methods; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000469:parasitology* / Q000473:pathology*; D051379:Mice