Design and Synthesis of Peptide‐Polyester Conjugates for Cell‐Mediated Scaffold Degradation

Biodegradable polyesters are promising biomaterials for tissue engineering. Polycaprolactone (PCL) is particularly attractive for orthopedic applications like craniofacial bone repair but does not degrade at the same rate as new tissue formation, which may compromise functional regeneration. To address this, we incorporated a protease-cleavable peptide directly into the PCL backbone. A functional mass spectrometry approach was used to identify a fast-degrading peptide (Fast) selectively cleaved by multiple cell types. Conjugates containing Fast or its scrambled control (ScrFast) were solvent-cast with an RGDS-PCL conjugate into disks. Including Fast and ScrFast peptides did not impair cell adhesion. Cy3-labeling enabled real-time quantification of degradation in the presence of collagenase or human mesenchymal stromal cells (hMSCs). After 21 days in collagenase, Fast-PCL released 20.38 ± 2.17 nmol Cy3 (25.77% ± 3.70%) vs. 8.70 ± 0.92 nmol (11.31% ± 1.01%) for ScrFast-PCL with respective mass losses of 22.1% ± 1.2%, and 18.9 ± 3.8%, indicating enzyme-mediated degradation. Under hMSC-mediated degradation, Fast-PCL released 30.31 ± 3.18 nmol Cy3 (26.68% ± 2.17%) compared to 23.91 ± 2.13 nmol (18.97% ± 1.24%) from ScrFast-PCL, indicating sequence-dependent, cell-directed resorption. This platform integrating protease-sensitive peptides into the polymer backbone can be leveraged to couple scaffold remodeling to enhance tissue regeneration.