A 3D Bioprinted Material That Recapitulates the Perivascular Bone Marrow Structure for Sustained Hematopoietic and Cancer Models

Abstract

Translational medicine requires facile experimental systems to replicate the dynamic biological systems of diseases. Drug approval continues to lag, partly due to incongruencies in the research pipeline that traditionally involve 2D models, which could be improved with 3D models. The bone marrow (BM) poses challenges to harvest as an intact organ, making it difficult to study disease processes such as breast cancer (BC) survival in BM, and to effective evaluation of drug response in BM. Furthermore, it is a challenge to develop 3D BM structures due to its weak physical properties, and complex hierarchical structure and cellular landscape. To address this, we leveraged 3D bioprinting to create a BM structure with varied methylcellulose (M): alginate (A) ratios. We selected hydrogels containing 4% (w/v) M and 2% (w/v) A, which recapitulates rheological and ultrastructural features of the BM while maintaining stability in culture. This hydrogel sustained the culture of two key primary BM microenvironmental cells found at the perivascular region, mesenchymal stem cells and endothelial cells. More importantly, the scaffold showed evidence of cell autonomous dedifferentiation of BC cells to cancer stem cell properties. This scaffold could be the platform to create BM models for various diseases and also for drug screening.

Current Advances in 3D Bioprinting for Cancer Modeling and Personalized Medicine

“…In all these conditions, upregulation of cancer stem cell marker genes is observed (Oct3/4, Nanog and Sox 2). Similarly, including cancer cells in alginate beads, in alginate/chitosan, chitosan/hyaluronic acid, or collagen hydrogel, increases the proportion of CSC with an upregulation of stemness genes for glioblastoma, breast, hepatocellular, and prostate cancer [155][156][157][158][159][160][161]. Similar results can be obtained with fibrous materials made of PCL [162].…”

Current Advances in 3D Bioprinting for Cancer Modeling and Personalized Medicine

“…In all these conditions, upregulation of cancer stem cell marker genes is observed (Oct3/4, Nanog, and Sox 2). Similarly, including cancer cells in alginate beads, alginate/chitosan, chitosan/hyaluronic acid, or collagen hydrogel increases the proportion of CSC with an upregulation of stemness genes for glioblastoma, breast, hepatocellular, and prostate cancer [ 36 , 171 , 172 , 173 , 174 , 175 , 176 ]. Similar results can be obtained with fibrous materials made of PCL [ 177 ].…”

Engineering strategies to achieve efficient in vitro expansion of haematopoietic stem cells: development and improvement

“…The combination of 6% methylcellulose and 2% alginate was found to best mimic the optional properties of bone marrow properties, such as the overall structure, oxygen availability and rheological properties. 188 Braham et al then added an additional external mechanical stimulus, intermittent hydrostatic pressure (IHP), based on sodium alginate to simulate the mechanical environment of osteoblasts within the bone marrow. The combination of osteoblasts and IHP resulted in an increase in the migration rate of HSCs while maintaining a high survival rate.…”