A Vascularized Bone Marrow Model for In Vitro Testing of Drug Toxicity

PROJECT SUMMARY The primary function of the bone marrow is hematopoiesis -- the production of leukocytes (white blood cells), erythrocytes (red blood cells), and platelets to perform the essential functions of blood. Blood cells have a limited lifespan ranging from days (leukocytes) to months (erythrocytes), and thus have to be regularly replaced. This function is accomplished by hematopoietic stem/progenitor cells (HSPCs) which rapidly and regularly differentiate to produce nearly 200 billion cells each day, but also exists in specialized niches within the bone marrow to maintain their stem cell state. Because of their regular and rapid differentiation, HSPCs are susceptible to drugs which target rapidly dividing cells, such as chemotherapeutics for cancer, as well as a host of other non-cancer drugs. As such, assessing potential bone marrow toxicity is critical in the drug development pipeline. To assess toxicity (and efficacy), the emerging field of microphysiological systems (MPS) or “organ-on-a-chip” provides human cell/tissue models to enhance the efficiency of pre-clinical testing during drug development. The primary goal of this Phase I SBIR application is to demonstrate the feasibility of a proprietary technology of Aracari, an early stage medical device company, to model appropriate drug responses of human bone marrow in vitro. The project leverages Aracari’s patented core technology – 3D perfusable living human vascular networks – to create a vascularized micro-bone marrow, or VMBMTM. The 3D vascular network in the VMBM recreates the perivascular niche of the bone marrow, thought to be critical to maintain a small population of HSPCs as well as guide differentiation into myeloid and erythroid lineages. The specific aims are to: 1) test the ability of the VMBM to capture bone marrow toxicity using a small panel of drugs (Teniposide, Alemtuzumab, and Paclitaxel) that demonstrate well-documented, as well as unexpected at the time of human trials, toxicity to bone marrow manifested as neutropenia, but act through different mechanisms; and, 2) Test the ability of the VMBM to model the effect of bone marrow protective drugs using a small panel of commercially available drugs that are known to stimulate production of neutrophils (NeupogenÒ (filgrastim)), and red blood cells (erythropoietin) by the bone marrow. The development of Aracari’s VMBM represents a significant advance in technology to assess bone marrow toxicity to not only chemotherapy drugs for cancer, but a much wider range of drugs that potentially impact bone marrow function. Upon completion of the proposed Phase I feasibility study, the plans for a Phase II application would focus on a broader range of variables that could impact drug response (e.g., sex, age, race) as well as the critical next step in the commercialization process – production and scale-up.