Development of multicompartment biomaterials to modulate cellular environments for improved tendon-to-bone rotator cuff repair

Rotator cuff tears present a growing clinical challenge due to both the continual rise in the number of patients and the inability of current methods to facilitate regenerative healing, resulting in significant re-failure rates. Current surgical repair methods rely on the mechanical reattachment of the torn tendon back to the bone. However, these techniques fail to account for the crucial interfacial tissue that mechanically integrates highly dissimilar tendon and bone regions at the osteotendinous junction, known as the enthesis. Here, unmineralized and mineralized fibrocartilage regions provide a graded transition in structure between aligned tendon and unaligned bone, shielding the interface from detrimental concentrations of localized strain that could induce overall failure. Further, the tendon, unmineralized fibrocartilage, mineralized fibrocartilage, and bone contain unique populations of cells, giving rise to spatially distinct environments of small biomolecule signaling and cell-cell interaction. Given the complexity of this region and the current shortcomings in surgical repair, biomaterials strategies for regeneration of the enthesis offer a promising avenue for next-generation rotator cuff repair. Our lab has developed variations of collagen-glycosaminoglycan scaffolds that can guide mesenchymal stem cell behavior toward tenogenic or osteogenic lineages. Additionally, our lab has described designs for multicompartment scaffolds, incorporating these scaffold variants into a single material for use in tendon-to-bone enthesis regeneration. The most recent design utilizes a compliant, enzymatically cross-linked hydrogel that integrates aligned, non-mineralized tendon-specific and isotropic, mineralized bone-specific collagen scaffold compartments to form a triphasic scaffold. However, despite demonstrating preliminary mechanical promise, the biological implications of such a design were not considered. This thesis focuses on the development of a triphasic scaffold to guide region-specific osteotendinous cell behavior. We first evaluate cellular crosstalk between the individual compartments, establishing a biologically favorable hydrogel construct for use in the triphasic design and reinforcing the importance of all three scaffold compartments for a functional interfacial material. Next, we investigate the optimization of the interfacial hydrogel for improved mechanical compliance, material integration, and promotion of a fibrocartilaginous phenotype via chemical modification of the backbone polymer and selective incorporation of bioactive supplements. Finally, we extend our scope of biomaterials analysis to consider greater environmental complexity and outside stimuli through the incorporation of cyclic tensile loading and the development of a miniaturized multicompartment model for use with in vivo analysis. Altogether, this dissertation explores the development of materials for interfacial tissue engineering applications, establishing the importance of crosstalk between local cell populations and of cross-interaction between material, mechanical, and biological properties to demonstrate the importance of system-level consideration in biomaterial design.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Timmer, Kyle Benjamin

Contributors dc:contributor

• Harley, Brendan A.
• Harley, Brendan A
• Rogers, Simon A
• Kong, Hyunjoon
• Killian, Megan L.

• Enthesis
• Scaffold
• Triphasic
• Multicompartment
• Biomaterial

Statement dc:rights

• Copyright 2025 Kyle Timmer

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/129854

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F129854