Cartilage loss is a leading cause of disability among adults and effective therapy remains elusive. Neonatal chondrocytes (NChons) are an attractive allogeneic cell source for cartilage repair, but their clinical translation has been hindered by scarce donor availability. Here we examine the potential for catalyzing cartilage tissue formation using a minimal number of NChons by co-culturing them with adipose-derived stem cells (ADSCs) in 3D hydrogels. Using three different co-culture models, we demonstrated that the effects of co-culture on cartilage tissue formation are dependent on the intercellular distance and cell distribution in 3D. Unexpectedly, increasing ADSC ratio in mixed co-culture led to increased synergy between NChons and ADSCs, and resulted in the formation of large neocartilage nodules. This work raises the potential of utilizing stem cells to catalyze tissue formation by neonatal chondrocytes via paracrine signaling, and highlights the importance of controlling cell distribution in 3D matrices to achieve optimal synergy.C artilage loss is a leading cause of disability among adults and represents a huge socio-economical burden.Articular cartilage has limited self-repair potential and damage is often irreversible 1 . Conventional cellbased therapy utilizes autologous chondrocytes for cartilage repair, which is associated with several shortcomings including donor site morbidity and the need for in vitro expansion and multiple surgeries 2 . Furthermore, the ability of autologous chondrocytes to regenerate cartilage tissue declines rapidly with patient age and in vitro expansion 3,4 , making them a suboptimal cell source for cartilage repair. Unlike autologous adult chondrocytes, allogeneic neonatal chondrocytes (NChons) are highly proliferative, immune-privileged, and can readily produce abundant cartilage matrix 3,5,6 . However, donor availability for NChons is scarce, which greatly hinders their broad application.In addition to chondrocytes, adult mesenchymal stem cells (MSCs) are an alternative cell source for cartilage repair 7 . Adipose-derived stem cells (ADSCs), in particular, are an attractive candidate due to their ease of isolation, relative abundance, and chondrogenic potential 8,9 . While stem cells are widely known for their potential to promote tissue regeneration through lineage-specific differentiation, emerging evidence suggests that paracrine signals secreted by stem cells may also contribute to tissue repair 10,11 . Several studies have examined the interactions between articular chondrocytes and MSCs; however, the reported results have been contradictory. While some studies indicated that MSCs inhibit cartilage production by chondrocytes 12,13 , others showed that MSCs stimulate chondrocyte proliferation and cartilage matrix production [14][15][16][17][18] . The discrepant findings may be due to the differences in various parameters in these studies such as co-culture models, medium composition (i.e. serum or other growth factor supplementation), and donor age or disease phenoty...
Osseointegration of porous-coated implants during revision arthroplasty procedures is often impeded due to the presence of residual granuloma, particulate debris, and a sclerotic, dysvascular bone bed. We hypothesized that local infusion of recombinant fibroblast growth factor (FGF-2) would increase bone ingrowth in an in vivo model of tissue differentiation in the rabbit tibia in the presence of phagocytosable polyethylene particles. A drug test chamber (DTC) was implanted in the proximal medial tibial metaphysis of mature rabbits unilaterally. The chamber contained a 1x 1 x 5-mm tunnel for tissue ingrowth, and was connected to an osmotic diffusion pump. FGF-2 was infused at dosages of 0, 0.5, 5, 50, or 500 ng/day for a 3-week period, with subsequent harvesting of the ingrown tissue after each 3-week treatment. The effects of ultrahigh molecular weight polyethylene particles (0.5-microm diameter) on tissue ingrowth were determined by adding particles to the chamber at concentrations of 5.8 x 10(11) (low dose) or 1.7 x 10(12) (high dose) particles/mL, with and without infusion of 50 ng/day of FGF for 3 weeks. The tissue forming in the chamber was harvested after each treatment for histologic processing and morphometric analysis of bone ingrowth. Statistical analysis was performed using parametric tests (ANOVA), nonparametric tests (Kruskal-Wallis test) and post hoc tests. In the absence of particles, infusion of 50 ng FGF-2 per day yielded the greatest amount of bone ingrowth. The high dose of particles suppressed bone ingrowth into the chamber, but the low dose particles did not (p = 0.0002, 95% confidence limits = 9.19-18.80). Infusion of 50 ng FGF-2 per day significantly increased net bone formation in the presence of high-dose UHMWPE particles (p = 0.039, 95% confidence limits = 1.41-6.79). There was a trend for decreased numbers of vitronectin-receptor positive (osteoclast-like) cells with the addition of FGF-2, compared to particles alone (p = 0.08). Local delivery of FGF-2 may prove useful in mitigating the adverse effects of wear debris (e.g., in treating early osteolytic lesions), and facilitating osseointegration of revision total joint replacements in situations where the bone bed is suboptimal and residual particles and granulomatous tissue are present.
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