טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAppelman Taly
SubjectThe Differential Effect of Scaffold Composition and
Architecture on Chondrogenic Response to
Mechanical Stimulation
DepartmentDepartment of Biomedical Engineering
Supervisors Professor Dror Seliktar
Professor Emeritus Joseph Mizrahi
Full Thesis textFull thesis text - English Version


Abstract

A hydrogel scaffold system with tunable bioactivity and a mechanical stimulation bioreactor were used for cartilage tissue engineering with the motivation of understanding the importance of scaffold bioactivity in chondrocyte response to dynamic stimulation. Protein and proteoglycans were conjugated to functionalized poly(ethylene glycol) (PEG) and immobilized in a PEG hydrogel to create bio-synthetic materials. Four different bio-synthetic compositions were tested in this study, including: PEG-Proteoglycan (PP), PEG-fibrinogen (PF), PEG-Albumin (PA), and PEG only. The PP and PF represented the instructive hydrogels which contained cell-adhesive ECM proteins for cell signaling; the PA and PEG only represented the permissive hydrogels. The influence of the bioactive elements of the scaffold was investigated under large strain deformations (15%, at 1 Hz) of chondrocyte-seeded constructs for up to 28 days. Mechanical stimulation had a beneficial effect on the chondrocyte response as measured by the compressive modulus of the constructs, cell number, glycosaminoglycans (GAGs) and collagen type II accumulation inside the constructs. The composition of the scaffold significantly affected this response, except for cell number. Stimulation also inhibited the production of collagen type I, an indicator for chondrocyte de-differentiation. Swelling ratio of the constructs decreased due to the stimulation and cell viability remained high in all scaffold types. Correlation maps between scaffold properties underscore the differences between permissive and instructive scaffolds in this regard. These findings indicate that while dynamic stimulation causes metabolic changes in chondrocytes seeded in PEG hydrogels, the matrix bioactivity has a significant role in chondrocyte mechanotransduction. In order to examine the mechanisms underlying remodeling, adaptation and degeneration of neo-cartilage subjected to dynamic loads, it is also important to know the stress-strain state in the encapsulated chondrocytes. In this context, a finite element analysis of chondrocyte compression was performed using several constitutive models to simulate the mechanical behavior of the different cell embedded scaffolds and to describe the stress-strain state in the chondrocytes during unconfined compression. Material modulus, cell size and pericellular matrix (PCM) accumulation affected stresses and strains, values and spatial distributions at the cellular subdomain and cell-matrix boundary. Constitutive modeling also affected the absolute values though usually a similar trend was observed.