Three-dimensional osteochondral microtissue to model pathogenesis of osteoarthritis

Abstract

Osteoarthritis (OA), the most prevalent form of arthritis, affects up to 15% of the adult population and is principally characterized by degeneration of the articular cartilage component of the joint, often with accompanying subchondral bone lesions. Understanding the mechanisms underlying the pathogenesis of OA is important for the rational development of disease-modifying OA drugs. While most studies on OA have focused on the investigation of either the cartilage or the bone component of the articular joint, the osteochondral complex represents a more physiologically relevant target because the disease ultimately is a disorder of osteochondral integrity and function. In our current investigation, we are constructing an in vitro three-dimensional microsystem that models the structure and biology of the osteochondral complex of the articular joint. Osteogenic and chondrogenic tissue components are produced using adult human mesenchymal stem cells derived from bone marrow and adipose seeded within biomaterial scaffolds photostereolithographically fabricated with defined internal architecture. A three-dimensional-printed, perfusion-ready container platform with dimensions to fit into a 96-well culture plate format is designed to house and maintain the osteochondral microsystem that has the following features: an anatomic cartilage/bone biphasic structure with a functional interface; all tissue components derived from a single adult mesenchymal stem cell source to eliminate possible age/tissue-type incompatibility; individual compartments to constitute separate microenvironment for the synovial and osseous components; accessible individual compartments that may be controlled and regulated via the introduction of bioactive agents or candidate effector cells, and tissue/medium sampling and compositional assays; and compatibility with the application of mechanical load and perturbation. The consequences of mechanical injury, exposure to inflammatory cytokines, and compromised bone quality on degenerative changes in the cartilage component are examined in the osteochondral microsystem as a first step towards its eventual application as an improved and high-throughput in vitro model for prediction of efficacy, safety, bioavailability, and toxicology outcomes for candidate disease-modifying OA drugs.

3-D Structural Changes in Subchondral Bone and the Effect of Bisphosphonate Intervention in Early Osteoarthritis

“…However, the repair and reconstruction of the subchondral bone in the later stage led to sclerosis, and hardening of the subchondral area. This uneven hardening altered the force balance on the articular cartilage, and increased the cartilage damage, although this effect was not observed in the Bis group, indicating that bisphosphonate promoted repair of the damaged subchondral bone (Lozito et al, 2013). In addition, the general condition of the articular cartilage in the Bis group was also significantly better than in the model group, which indicates that bisphosphonate might be used to treat the articular cartilage damage associated with OA.…”

Three-dimensional printing in surgery: a review of current surgical applications

“…In the field of orthopedics, 3D printing was utilized in the fabrication of a container to research osteoarthritis in-vitro. 49 The precision of and accuracy of modern 3D printers has made this possible and the experimental set-up allowed for the effects of various modulators to be assessed in-vitro.…”

Challenges in engineering osteochondral tissue grafts with hierarchical structures

“…The cells from this middle layer formed the ZCC 112 . Very similar approach for OC interface forming by placing a layer of MSC-laden collagen type I hydrogel between the chondral and osseous layers was implemented by Lozito et al when constructing the 3D osteochondral microtissues, described in detail in the next section 23 .…”

“…Lozito et al constructed an in vitro system with three-dimensional (3D) microtissues designed for biological studies of the osteochondral complex of the articular joint 23 . The model was constructed by seeding hMSCs from bone marrow and adipose tissue aspirates into photo-stereolithographically fabricated biomaterial scaffolds with defined internal architectures.…”

“…Osteochondral grafts can also serve as in vitro pre-clinical models for studies of disease pathology, identification of therapeutic targets, and evaluation of drug toxicity and efficacy 22, 23 .…”