Growing Pains: The Need for Engineered Platforms to Study Growth Plate Biology

Abstract

Growth plates, or physis, are highly specialized cartilage tissues responsible for longitudinal bone growth in children and adolescents. Chondrocytes that reside in growth plates are organized into three distinct zones essential for proper function. Modeling key features of growth plates may provide an avenue to develop advanced tissue engineering strategies and perspectives for cartilage and bone regenerative medicine applications and a platform to study processes linked to disease progression. In this review, a brief introduction of the growth plates and their role in skeletal development is first provided. Injuries and diseases of the growth plates as well as physiological and pathological mechanisms associated with remodeling and disease progression are discussed. Growth plate biology, namely, its architecture and extracellular matrix organization, resident cell types, and growth factor signaling are then focused. Next, opportunities and challenges for developing 3D biomaterial models to study aspects of growth plate biology and disease in vitro are discussed. Finally, opportunities for increasingly sophisticated in vitro biomaterial models of the growth plate to study spatiotemporal aspects of growth plate remodeling, to investigate multicellular signaling underlying growth plate biology, and to develop platforms that address key roadblocks to in vivo musculoskeletal tissue engineering applications are described.

Keywords: bones; cartilages; growth plates; physis; tissue engineering.

Figure 1

Injury and disease that occur at the growth plates. The growth plates, or physis, can be injured due to A) fractures which are classified into Salter‐Harris fractures based on the injury location, B) genetic disorders which can alter the cellular signaling and matrix composition of the growth plates, and C) cancers which can occur at or near the growth plates and influence cell biology, matrix composition, and tissue stiffness. In each instance, the cell biology is and the extracellular matrix are altered which causes severe issues during skeletal development. Figure created with BioRender.com.

Figure 2

The architecture of the growth plates. The growth plates, or physis, are highly organized cartilage tissues located between the epiphysis and metaphysis of the long bones. They are composed of chondrocytes embedded in an extracellular matrix and contain three distinct zones: resting, proliferative, and hypertrophic. Vasculature from the epiphysis and metaphysis provide nutrients to cells in the resting and hypertrophic zones. Figure created with BioRender.com.

Figure 3

Extracellular matrix composition of the growth plates. The growth plates, or physis, contain multiple matrix proteins that are critical to their function. Hyaluronic acid and aggrecan aggregates along with collagen II are present in each growth plate zone. Matrix vesicles and free hyaluronic acid are most present in the hypertrophic zone, and collagen X is present exclusively in the hypertrophic zone. Figure created with BioRender.com.

Figure 4

Methods for studying growth plate biology in 3D. A) Explant culture is the in vitro culture of living tissues, organs, or cells. B) Cell pellet cultures are created by centrifuging cells and then culturing the resulting pellets in media. C) Biomaterials allow the control of extracellular matrix, cellular, and growth factor composition for the in vitro study of biological systems. Figure created with BioRender.com.