The influence of collagen-GAG scaffold architectural and biological cues on tenocyte and mesenchymal stem cell bioactivity for musculoskeletal tissue engineering

While many tissue engineering strategies focus on repair of single tissues, orthopedic injuries often occur at the interface between soft tissue and bone. The tendon-bone junction (TBJ) is a classic example of such an interface, and contains overlapping patterns of growth factors, extracellular matrix (ECM) proteins, and mineral content that serve to minimize stress concentrations and enable normal locomotion. Clinical strategies to treat TBJ injuries forsake biological integration for mechanical fixation, resulting in high failure rates. Modern tissue engineering requires the design of new biomaterials permitting simultaneous control of microstructural, mechanical, and biochemical properties in a spatially-defined manner. This thesis describes a suite of studies undertaken to better understand microenvironmental regulators of cell bioactivity and the application of this knowledge to the design of a multi-compartment scaffold for engineering the TBJ. The studies here use collagen-glycosaminoglycan (CG) scaffolds, regulatory compliant analogs of the native ECM that have been applied to the regeneration of dermis, peripheral nerve, and osteochondral tissue. Chapter 2 quantifies the role CG scaffold relative density plays in directing tenocyte bioactivity and maintaining transcriptomic stability. Chapter 3 describes an investigation elucidating the influence of the dose and mode of presentation (soluble, sequestered) of five biomolecules (SDF-1α, PDGF-BB, IGF-1, bFGF, and GDF-5) on the recruitment, proliferation, collagen synthesis, and genomic stability of tenocytes within anisotropic CG scaffolds. Chapter 4 uses selective modification of our standard CG scaffold to probe the combined influences of structural and biochemical instructive cues to drive human bone marrow-derived mesenchymal stem cell (MSC) differentiation down tenogenic, osteogenic, and chondrogenic lineages respectively. Chapter 5 utilizes a series of CG scaffolds that were inspired by elements of distinct components of orthopedic interfaces (cartilage, tendon/ligament, and bone) to examine the role of biomaterial physical properties (relative density, mineral content) on biasing MSC phenotype in the presence of mixed soluble signals to drive osteogenesis or chondrogenesis. Finally, chapter 6 adapts the CG scaffold system to provide a pathway towards engineering the TBJ. 3D scaffolds with coincident gradients of pore anisotropy and mineral content to drive spatially-graded MSC differentiation were fabricated for the first time. Together, these studies present the framework for building instructive biomaterials to regulate stem cell fate in the context of musculoskeletal tissue repair.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2013

Author dc:creator

• Caliari, Steven R.

Contributors dc:contributor

• Harley, Brendan A.
• Higdon, Jonathan J.L.
• Bailey, Ryan C.
• Rao, Christopher V.
• Kong, Hyun Joon

• Tissue engineering
• regenerative medicine
• mesenchymal stem cells
• collagen
• tendon
• freeze-drying
• scaffold
• orthopedic interfaces

Statement dc:rights

• Copyright 2013 Steven Richard Caliari

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/45575

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/45575