Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study

Background A common approach for tissue regeneration is cell delivery, for example by direct transplantation of stem or progenitor cells. An alternative, by recruitment of endogenous cells, needs experimental evidence. We tested the hypothesis that the articular surface of the synovial joint can regenerate with a biological cue spatially embedded in an anatomically correct bioscaffold. Methods In this proof of concept study, the surface morphology of a rabbit proximal humeral joint was captured with laser scanning and reconstructed by computer-aided design. We fabricated an anatomically correct bioscaffold using a composite of poly-e-caprolactone and hydroxyapatite. The entire articular surface of unilateral proximal humeral condyles of skeletally mature rabbits was surgically excised and replaced with bioscaffolds spatially infused with transforming growth factor beta 3 (TGF beta 3)-adsorbed or TGF beta 3-free collagen hydrogel. Locomotion and weightbearing were assessed 1-2, 3-4, and 5-8 weeks after surgery. At 4 months, regenerated cartilage samples were retrieved from in vivo and assessed for surface fissure, thickness, density, chondrocyte numbers, collagen type II and aggrecan, and mechanical properties. Findings Ten rabbits received TGF beta 3-infused bioscaffolds, ten received TGF beta 3-free bioscaffolds, and three rabbits underwent humeral-head excision without bioscaffold replacement. All animals in the TGF beta 3-delivery group fully resumed weightbearing and locomotion 3-4 weeks after surgery, more consistently than those in the TGF beta 3-free group. Defect-only rabbits limped at all times. 4 months after surgery, TGF beta 3-infused bioscaffolds were fully covered with hyaline cartilage in the articular surface. TGF beta 3-free bioscaffolds had only isolated cartilage formation, and no cartilage formation occurred in defect-only rabbits. TGF beta 3 delivery yielded uniformly distributed chondrocytes in a matrix with collagen type II and aggrecan and had significantly greater thickness (p=0.044) and density (p<0.0001) than did cartilage formed without TGF beta 3. Compressive and shear properties of TGF beta 3-mediated articular cartilage did not differ from those of native articular cartilage, and were significantly greater than those of cartilage formed without TGF beta 3. Regenerated cartilage was avascular and integrated with regenerated subchondral bone that had well defined blood vessels. TGF beta 3 delivery recruited roughly 130% more cells in the regenerated articular cartilage than did spontaneous cell migration without TGF beta 3. Interpretation Our findings suggest that the entire articular surface of the synovial joint can regenerate without cell transplantation. Regeneration of complex tissues is probable by homing of endogenous cells, as exemplified by stratified avascular cartilage and vascularised bone. Whether cell homing acts as an adjunctive or alternative approach of cell delivery for regeneration of tissues with different organisational complexity warrants further investigation.