Abstract
We have recently identified novel small molecules, Oxo-M and 4-PPBP, which specifically stimulate endogenous tendon stem/progenitor cells (TSCs), leading to potential regenerative healing of fully transected tendons. Here, we investigated an injectable, multidomain peptide (MDP) hydrogel providing controlled delivery of the small molecules for regenerative tendon healing. We investigated the release kinetics of Oxo-M and 4-PPBP from MDP hydrogels and the effect of MDP-released small molecules on tenogenic differentiation of TSCs and in vivo tendon healing. In vitro, MDP showed a sustained release of Oxo-M and 4-PPBP and a slower degradation than fibrin. In addition, tenogenic gene expression was significantly increased in TSC with MDP-released Oxo-M and 4-PPBP as compared to the fibrin-released. In vivo, MDP releasing Oxo-M and 4-PPBP significantly improved tendon healing, likely associated with prolonged effects of Oxo-M and 4-PPBP on suppression of M1 macrophages and promotion of M2 macrophages. Comprehensive analyses including histomorphology, digital image processing, and modulus mapping with nanoindentation consistently suggested that Oxo-M and 4-PPBP delivered via MDP further improved tendon healing as compared to fibrin-based delivery. In conclusion, MDP delivered with Oxo-M and 4-PPBP may serve as an efficient regenerative therapeutic for in situ tendon regeneration and healing.
Highlights
Expressions of tendon-related genes, including COL-I and III, Tn-C, TnmD, Fn, and Scx, were significantly increased in tendon stem/progenitor cells (TSCs) cultured under a Trans-well insert loaded with Oxo-M and 4-PPBP in fibrin or multidomain peptide (MDP) hydrogel, in comparison with control with no treatment by 1 week (Figure 1D) (n = 5 per group; p < 0.001)
All the tested tenogenic gene expressions were significantly higher in MDP + OP than in Fib + OP (Figure 1E) (n = 5 per group; p < 0.001), suggesting a positive effect of the prolonged-release from MDP hydrogel
Our findings suggest an effective and reliable approach to enable the controlled delivery of small molecules that improve regenerative tendon healing by harnessing endogenous stem/ progenitor cells
Summary
Tendons are dense fibrous tissues with the primary function of transferring mechanical forces from muscle to bone. Approximately 11% of runners in the US suffer from Achilles tendinopathy (Chen et al, 2009), and there are 5 million new cases of tennis elbow (lateral epicondylitis) each year (Chen et al, 2009). This results in an enormous healthcare burden, with treatment for tendon injuries exceeding $30 billion per year in the US alone (Chen et al, 2009; Kew et al, 2011). Injuries to adult tendons do not spontaneously heal and frequently end up with scar-like tissue—exhibiting high cellularity, disarrayed collagen fibers, and poor mechanical properties (Thomopoulos et al, 2003; Voleti et al, 2012)
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