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

Abstract

Summary 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-ε-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 β3 (TGFβ3)-adsorbed or TGFβ3-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 TGFβ3-infused bioscaffolds, ten received TGFβ3-free bioscaffolds, and three rabbits underwent humeral-head excision without bioscaffold replacement. All animals in the TGFβ3-delivery group fully resumed weightbearing and locomotion 3–4 weeks after surgery, more consistently than those in the TGFβ3-free group. Defect-only rabbits limped at all times. 4 months after surgery, TGFβ3-infused bioscaffolds were fully covered with hyaline cartilage in the articular surface. TGFβ3-free bioscaffolds had only isolated cartilage formation, and no cartilage formation occurred in defect-only rabbits. TGFβ3 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 TGFβ3. Compressive and shear properties of TGFβ3-mediated articular cartilage did not differ from those of native articular cartilage, and were significantly greater than those of cartilage formed without TGFβ3. Regenerated cartilage was avascular and integrated with regenerated subchondral bone that had well defined blood vessels. TGFβ3 delivery recruited roughly 130% more cells in the regenerated articular cartilage than did spontaneous cell migration without TGFβ3. 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 a vascular 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. Funding New York State Stem Cell Science; US National In...

Evaluation of the Early In Vivo Response of a Functionally Graded Macroporous Scaffold in an Osteochondral Defect in a Rabbit Model

“…This correlates well with other studies, where cartilage repair was attributed to cell homing, engraftment and repair due to pore architecture of the construct used. 4,9,19 Despite that collagen type I staining was observed in all defects in the present study, chondrocytes adjacent to the cell-free construct did not stain positive. Although, collagen type I is associated with fibrocartilage repair, spatial and temporal patterns of collagen type I expression have been observed during cartilage development, 26 at early time points during in vitro chondrogenesis of MSC 14 and after ACI in humans.…”

“…1A illustrateds the generation of a biomimetic pore structure, with an open tunnel system, created by the customdesigned layer structure. In addition to creating an open functionally-graded pore template for cells that complements the work of Chou et al 4 and Lee et al, 19 the compressive modulus values were orders of magnitude higher (10 MPa) than previous composite constructs 27 (0.005-0.10 MPa) and represent a step towards mechanical property values proposed for hyaline cartilage regeneration in the region 1-12MPa. 12 However, it must be noted that compression testing of the macroporous PLCL scaffolds was performed on dry samples at room temperature and that future studies will be conducted to examine the mechanical properties of constructs stored 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Previous studies have successfully employed bone marrow-derived MSCs for cartilage repair applications.…”

“…In a recent study by Lee et al, 19 it was suggested that a functionally-graded pore architecture promoted endogenous cell recruitment and provided a superior support structure for cartilage repair. To achieve this specific functionality, a support structured was designed and fabricated to mimic both the structure and mechanical properties of native articular cartilage repair.…”

“…12 Using this approach, Malda et al pores on the bottom surface that displayed promising cartilage repair in vivo. 19 More 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 recently, Mendoza-Palomares et al developed a smart hybrid system equipped with nanoreservoirs of therapeutic agents, which promoted cartilage repair in an osteochondral defect. 24 These studies present an alternative approach to that of scaffolds seeded with cells to promote hyaline cartilage repair.…”

Evaluation of Cartilage Repair by Mesenchymal Stem Cells Seeded on a PEOT/PBT Scaffold in an Osteochondral Defect

“…In terms of materials degradation, the slower degradation of the PEOT/PBT scaffold agrees with other studies 9,27 , in particular where cell-free and cell-seeded polycaprolactone scaffold have 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 shown to aid repair in osteochondral defects in rabbit models, without showing evidence of bone cysts or inflammation 9 .…”