The repair of rotator cuff injury, as a primary cause of shoulder joint dysfunction, is clinically challenging due to the complexity of the bone-to-tendon interface, called enthesis. It is characterized by significant compositional, structural and mechanical differences with a gradual spatial transition from tendon to unmineralized fibrocartilage, mineralized fibrocartilage and bone. Therefore, the classic scaffold-based approach fails to support enthesis healing. Multiphasic and graded scaffolds containing biochemical gradient, such as growth factors, offer a biomimetic approach by replicating the hierarchical architecture of enthesis and offering spatial control over cell phenotypes and extracellular matrix (ECM) formation. The low stability and high doses of growth factors used diminish the therapeutical effect of their application.

To overcome these disadvantages, PhaseScaff proposes a biomimetic gradient scaffold with therapeutic metal ions (TMIs) and architectural features that will stimulate the specific cell responses and ECM formation for tendon-to-bone repair. Previously, we developed TMIs-doped bioceramics, as well as TMIs-polysaccharide complexes in the forms of scaffolds and microparticulate systems for bone tissue engineering and drug delivery applications. PhaseScaff goes beyond the classic design and fabricates a multifunctional scaffold that will: 1) stimulate bone formation by a gradient organic-inorganic part containing magnesium- and copper-doped bioactive ceramics and bioactive glass, and 2) support tendon repair, offering microchannel structure and zinc ions for cell alignment and ECM formation. We expect that the compositional gradient of the bone part and the architectural characteristics of the tendon part will achieve a gradual transition of cell phenotype and accommodate mechanical load transfer between the hard and soft tissue necessary for enthesis healing. The novel PhaseScaff materials with the ability to stimulate tendon and bone healing will contribute to the development of biomaterials for applications in regenerative medicine, orthopedics and personalized medical treatments, improving the quality of life of patients, and helping the national health strategy.

The main goal of PhaseScaff will be achieved through specific objectives:

O1 To prepare a composite with a compositional gradient of bioactive inorganic phase for bone regeneration. Polysaccharide-based scaffold modified by doped CaP and BG will be prepared with a compositional gradient from 0 to 20 wt% of inorganic phase. Mg-doped CaP and Cu-doped silicate-based BG will be combined to support bone formation.

O2 To prepare a polymer-based scaffold with an oriented structure for tendon repair. Polysaccharide-based scaffold with oriented microchannels and zinc ions will be synthesized to support tenocytes’ proliferation and alignment.

O3 To prepare a biomimetic gradient scaffold for bone-to-tendon interface repair. Polysaccharide-zinc scaffold with oriented microchannels will be fused with porous composite gradient scaffold to provide a graded microenvironment for different cell phenotypes.

O4 To validate the interactions between the scaffold and cells. Static cell cultures of mesenchymal stem cells and tenocytes will be performed to evaluate the performance of the prepared scaffolds.