3D bioprinted multi-layered cell constructs with gradient core-shell interface for tendon-to-bone tissue regeneration

Rotator cuff tears are common among physically active individuals and often require surgical intervention owing to their limited self-healing capacity. This study proposes a new bioprinting approach using bone- and tendon tissue-specific bioinks derived from decellularized extracellular matrix, supplemented with hydroxyapatite and TGF-β/poly(vinyl alcohol) to fabricate engineered tendon-to-bone complex tissue. To achieve this goal, a core-shell nozzle system attached to a bioprinter enables the effective and simultaneous fabrication of aligned tendon tissue, a gradient tendon-bone interface (TBI), and a mechanically improved bone region, mimicking the native tendon-to-bone structure. In vitro evaluation demonstrated the well-directed differentiation of human adipose stem cells towards osteogenic and tenogenic lineages in the bone and tendon constructs. In the graded TBI structure, further facilitated fibrocartilage formation and enhanced the integration of tendon-to-bone tissues compared to non-graded structures in vitro. Furthermore, using a rabbit rotator cuff tear model, implantation of the biologically graded constructs significantly promoted the rapid regeneration of full-thickness tendon-to-bone tissue, including the formation of a high-quality TBI in vivo. This bioprinting approach not only improved mechanical properties and tissue integration but also enhanced angiogenesis and extracellular matrix (ECM) formation, demonstrating its potential as a promising platform for the regeneration of tendon-to-bone complex tissues.