Biomaterials-integrated microphysiological bone marrow chip model

About This Grant

Project Summary Trabecular bone marrow contains two anatomically distinct yet functionally interdependent niches that support hematopoietic stem cells (HSCs): the endosteal niche, which promotes dormancy and self-renewal of long-term HSCs, and the vascular niche, which supports actively cycling short-term HSCs and ongoing hematopoiesis. These compartments coordinate bone remodeling and hematopoiesis, but the mechanisms underlying their integration remain poorly understood due to the anatomical inaccessibility of the bone cavity and the lack of physiologically relevant preclinical models. This proposal aims to develop a biomaterials-integrated bone–marrow microphysiological system (MPS) that recapitulates the structural and functional interdependence of the bone and marrow compartments and enables dynamic analysis of HSC behavior. The platform integrates two advanced biomaterials: demineralized bone paper (DBP), an osteoid-like matrix that supports osteoblast mineralization and osteoclast-mediated remodeling, and an inverted colloidal crystal (ICC) hydrogel scaffold that mimics the sinusoidal architecture of marrow and supports stromal–hematopoietic interactions. The central hypothesis is that integrating these components within a silicon-based perfusion chip will enable high-fidelity modeling of dynamic bone marrow niche processes with precise experimental control and microscopic access. Aim 1 will establish the bone–marrow MPS by seeding BMSCs and osteoblasts into their respective biomaterials, validating niche-specific stromal phenotypes, and recapitulating bone remodeling. CD34⁺ HSCs will then be introduced to assess how integrated versus separated configurations of the bone and marrow compartments differentially regulate HSC behavior. Aim 2 will validate the bone–marrow MPS by recapitulating autologous HSC transplantation scenarios following preconditioning. Donor-matched bone–marrow MPS units will be established, and HSCs derived from a different donor will be introduced with and without fractionated irradiation. By comparing HSC engraftment outcomes, the MPS’s ability to replicate known features of clinical transplantation will be demonstrated. This human-relevant bone–marrow MPS platform will provide new insights into bone–marrow crosstalk, preconditioning regimens, and HSC processes. It offers a scalable, high-resolution system for studying hematopoiesis, transplantation biology, and therapeutic interventions—aligned with NIH priorities in the NOSI: Bold New Bioengineering Research for Heart, Lung, Blood, and Sleep Disorders.