Aims/hypothesis Glycogen synthase kinase 3β (GSK-3β) is an enzyme that is suppressed by insulin and when elevated results in insulin resistance in skeletal muscle and diabetes.

Attachment of dissimilar materials is prone to failure due to stress concentrations that can arise at interfaces. A compositionally or structurally graded transition can dissipate these stress concentrations and thereby toughen an attachment. The interface between compliant tendon and stiff bone utilizes a monotonic change in hydroxylapatite mineral (“mineral”) content to produce a gradient in mechanical properties and mitigate stress concentrations. Previous efforts to mimic the natural tendon-to-bone attachment have included electrospun nanofibrous polymer scaffolds with gradients in mineral. Mineralization of the nanofiber scaffolds has typically been achieved using simulated body fluid (SBF). Depending on the specific formulation of SBF, mineral morphologies ranged from densely packed small crystals to platelike crystal florets. Although this mineralization of scaffolds produced increases in modulus, the peak modulus achieved remained significantly below that of bone. Missing from these prior empirical approaches was insight into the effect of mineral morphology on scaffold mechanics and on the potential for the approach to ultimately achieve moduli approaching that of bone. Here, we applied two mineralization methods to generate scaffolds with spatial gradations in mineral content, and developed methods to quantify the stiffening effects and evaluate them in the context of theoretical bounds. We asked whether either of the mineralization methods we developed holds potential to achieve adequate stiffening of the scaffold, and tested the hypothesis that the smoother, denser mineral coating could attain more potent stiffening effects. Testing this hypothesis required development of and comparison to homogenization bounds, and development of techniques to estimate mineral volume fractions and spatial gradations in modulus. For both mineralization strategies, energy dispersive x-ray analysis demonstrated the formation of linear gradients in mineral concentration along the length of the scaffolds, and Raman spectroscopic analysis revealed that the mineral produced was hydroxylapatite. Mechanical testing showed that the stiffness gradient using the new method was significantly steeper. By analyzing the scaffolds using micromechanical modeling techniques and extrapolating from our experimental results, we present evidence that the new mineralization protocol has the potential to achieve levels of stiffness adequate to contribute to enhanced repair of tendon-to-bone attachments.

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