*Review* **In Vitro Modeling of Non-Solid Tumors: How Far Can Tissue Engineering Go?**

#### **Sandra Clara-Trujillo 1,2,\*, Gloria Gallego Ferrer 1,2 and José Luis Gómez Ribelles 1,2**


Received: 29 June 2020; Accepted: 10 August 2020; Published: 11 August 2020

**Abstract:** In hematological malignancies, leukemias or myelomas, malignant cells present bone marrow (BM) homing, in which the niche contributes to tumor development and drug resistance. BM architecture, cellular and molecular composition and interactions define di fferential microenvironments that govern cell fate under physiological and pathological conditions and serve as a reference for the native biological landscape to be replicated in engineered platforms attempting to reproduce blood cancer behavior. This review summarizes the di fferent models used to e fficiently reproduce certain aspects of BM in vitro; however, they still lack the complexity of this tissue, which is relevant for fundamental aspects such as drug resistance development in multiple myeloma. Extracellular matrix composition, material topography, vascularization, cellular composition or stemness vs. di fferentiation balance are discussed as variables that could be rationally defined in tissue engineering approaches for achieving more relevant in vitro models. Fully humanized platforms closely resembling natural interactions still remain challenging and the question of to what extent accurate tissue complexity reproduction is essential to reliably predict drug responses is controversial. However, the contributions of these approaches to the fundamental knowledge of non-solid tumor biology, its regulation by niches, and the advance of personalized medicine are unquestionable.

**Keywords:** blood cancer; disease modeling; bone marrow; niche; microenvironment; tissue engineering; 3D models; tumor-on-a-chip; leukemia; myeloma
