A microphysiological model of bone development and regeneration

Abstract

Endochondral ossification (EO) is an essential biological process than underpins how human bones develop, grow, and heal in the event of a fracture. So much is unknown about this process, thus clinical manifestations of dysregulated EO cannot be adequately treated. This can be partially attributed to the absence of predictive in vitro models of musculoskeletal tissue development and healing, which are integral to the development and preclinical evaluation of novel therapeutics. Microphysiological systems, or organ-on-chip devices, are advanced in vitro models designed for improved biological relevance compared to traditional in vitro culture models. Here we develop a microphysiological model of vascular invasion into developing/regenerating bone, thereby mimicking the process of EO. This is achieved by integrating endothelial cells and organoids mimicking different stages of endochondral bone development within a microfluidic chip. This microphysiological model is able to recreate key events in EO, such as the changing angiogenic profile of a maturing cartilage analogue, and vascular induced expression of the pluripotent transcription factors SOX2 and OCT4 in the cartilage analogue. This system represents an advanced in vitro platform to further EO research, and may also serve as a modular unit to monitor drug responses on such processes as part of a multi-organ system.

Emergent mechanical control of vascular morphogenesis

“…To study the mechanics of vascular morphogenesis systematically, we adapted an in vitro microfluidic platform ( 29 , 30 ) to enable the formation of tissue-scale constructs for mechanical characterization and observation of vascular self-assembly in various coculture configurations of ECs [human umbilical vein ECs (HUVECs)] with stromal fibroblasts (normal human lung fibroblasts; Fig. 1A and fig.…”

Vascular microphysiological systems

“…Vascularized models of bone have also highlighted the relevance of vasculature in developing more complex tissue models. In a model of the osteochondral interface, endothelial cells enhanced MSC differentiation into chondrogenic and osteogenic lineages [27], and in a model of endochondral ossification, crosstalk between endothelial cells and cartilage induced expression of pluripotent transcription factors [28]. In addition to these multicellular tissue models, there is also a need for multiorgan models.…”

Human iPSCs as Model Systems for BMP-Related Rare Diseases

“…Based on person-centred biomedical data of the somatic cell donor (e.g., age, sex, ethnics, co-morbidities, medication, medical history), the goal for patient-specific disease modelling, as well as personalized drug screening and personalized medicine, may be to combine microfluidic organ-on-chip technology with BMP rare disease patient iPSC-derived cells in a 3D matrix (organoids), following the concept of "miniature twinning" [238,239]. Organ-on-chip, 3D organoid-onchip, or multi-organ-chip systems currently attract a lot of attention [240,241] and have been successfully applied in recent years to create complex laboratory model systems for, e.g., systemic COVID-19 research [240], blood-brain barrier function [242], and bone regeneration [243,244]. The integration of biosensors into those high-tech systems and the concomitant application of defined cell mechanics make them an even more versatile tool with which to study disease mechanisms and accelerate drug development (Figure 4).…”