Scientists at the University of Massachusetts (UMass) Amherst’s Institute for Applied Life Sciences (IALS) say they have developed a technique to replicate bone tissue complexity and bone remodeling processes. They believe their work could help researchers further their study of bone biology and assist in improving development of drugs for osteoporosis.

The team published its study “Trabecular bone organoid model for studying the regulation of localized bone remodeling” in Science Advances.

“Trabecular bone maintains physiological homeostasis and consistent structure and mass through repeated cycles of bone remodeling by means of tightly localized regulation. The molecular and cellular processes that regulate localized bone remodeling are poorly understood because of a lack of relevant experimental models,” write the investigators.

“A tissue-engineered model is described here that reproduces bone tissue complexity and bone remodeling processes with high fidelity and control. An osteoid-inspired biomaterial—demineralized bone paper—directs osteoblasts to deposit structural mineralized bone tissue and subsequently acquire the resting-state bone lining cell phenotype. These cells activate and shift their secretory profile to induce osteoclastogenesis in response to chemical stimulation.”

“Quantitative spatial mapping of cellular activities in resting and activated bone surface coculture showed that the resting-state bone lining cell network actively directs localized bone remodeling by means of paracrine signaling and cell-to-cell contact. This model may facilitate further investigation of trabecular bone niche biology.”

Trabecular bone, or spongy bone, is a light, porous bone enclosing numerous large spaces that give a honeycombed or spongy appearance. Trabecular bones ace like shock absorbers for the body, transferring mechanical loads from the articular surface to the cortical bone. These bones have a lower calcium content and more marrow content compared to cortical bone. Trabecular bone density decreases with aging.

“Bone is a multifunctional tissue not only maintaining mechanical stability, but also regulating blood-forming and blood mineral content,” says Jungwoo Lee, a chemical engineer. “However, investigating bone-remodeling biology is challenging because this process occurs inside the bone cavity. Hard and opaque bone tissue is difficult to access, thus creating realistic bone tissue models outside of the body will advance our understanding of fundamental bone biology, as well as provide new opportunities to model disease progression and screening drug responses.”

Bone remodeling is a lifelong process during which mature bone tissue is removed from the skeleton and new bone tissue is formed. These processes also control the replacement of bone after an injury and the micro-damage that occurs during normal daily activity. Bone development occurs in a layer-by-layer manner as first bone-forming cells deposit structural collagen that in turn mineralizes to become hard bone. This process is repeated to remodel and model bone tissue throughout life.

The UMass scientists took bovine bones from a local slaughterhouse, then cleaned and cut them into small chunks that they demineralized in a chemical process. To reproduce the bone-remodeling process, the team developed a novel biomaterial, demineralized bone paper, that mimics the dense structural matrix with thin sections of demineralized bovine compact bone. This material has a controlled thickness and surface area. It is mechanically durable and semitransparent, as well.

The demineralized bone paper supports the processes of osteoblasts and osteoclasts, which are cells that exclusively reside and function on the bone surface. Osteoclasts are responsible for aged bone resorption, and osteoblasts are responsible for new bone formation.

The bone paper serves as a functional template on which osteoblasts rapidly deposit structural minerals, guided by lamellar structure of the dense collagen, and form osteoid bone having a depth similar to that seen in a live organism, explains Lee, who adds that the material’s semitransparency makes it possible to monitor ongoing cellular processes with fluorescent microscopy, and it is thin but durable enough to be handled easily.

Bone paper can be produced in large quantities; the team was able to produce more than 5,000 pieces from one bovine femur.

Yongkuk Park, a chemical engineering grad student and the first author, says the trabecular bone model could be humanized for translational research by replacing bovine bones. Humanized trabecular bone models could improve the predictive power of pre-clinical studies and shorten the screening period for osteoporosis drugs. It could also help researchers facilitate the future study of numerous aspects of bone biology, adds Park.

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