Functional tissue engineering for tendon repair: A multidisciplinary strategy using mesenchymal stem cells, bioscaffolds, and mechanical stimulation

Abstract

Over the past 8 years, our group has been continuously improving tendon repair using a functional tissue engineering (FTE) paradigm. This paradigm was motivated by inconsistent clinical results after tendon repair and reconstruction, and the modest biomechanical improvements we observed after repair of rabbit central patellar tendon defects using mesenchymal stem cell-gelsuture constructs. Although possessing a significantly higher stiffness and failure force than for natural healing, these first generation constructs were quite weak compared to normal tendon. Fundamental to the new FTE paradigm was the need to determine in vivo forces to which the repair tissue might be exposed. We first recorded these force patterns in two normal tendon models and then compared these peak forces to those for repairs of central defects in the rabbit patellar tendon model (PT). Replacing the suture with end-posts in culture and lowering the mesenchymal stem cell (MSC) concentration of these constructs resulted in failure forces greater than peak in vivo forces that were measured for all the studied activities. Augmenting the gel with a type I collagen sponge further increased repair stiffness and maximum force, and resulted in the repair tangent stiffness matching normal stiffness up to peak in vivo forces. Mechanically stimulating these constructs in bioreactors further enhanced repair biomechanics compared to normal. We are now optimizing components of the mechanical signal that is delivered in culture to further improve construct and repair outcome. Our contributions in the area of tendon functional tissue engineering have the potential to create functional load-bearing repairs that will revolutionize surgical reconstruction after tendon and ligament injury. ß

The Role of Mechanical Loading in Tendon Development, Maintenance, Injury, and Repair

“…Tissue engineers are incorporating mechanical stimulation to enhance tendon tissue augmentations and replacements [134][135][136][137][138][139][140][141][142][143][144][145][146] . By mechanically preconditioning the tissue-engineered construct cell population prior to in vivo implantation, the cells may be better equipped to enhance the repair since they have been exposed to the appropriate mechanical environment 134,135 .…”

“…Given the importance of physiological loading to maintain tendon homeostasis, investigators have shown that applying load promotes a tendon-like phenotype in both two and threedimensional culture conditions [139][140][141][142][143][144][145][146] . Ralphs et al showed that when tendon cells are cultured on a two-dimensional substrate and subjected to biaxial strain at 1 Hz for eight hours per day for a total of ninety-six hours, cells link together using actin adherens junctions along the principal line of strain to monitor tensile load 142 .…”

Substrate topography: A valuable in vitro tool, but a clinical red herring for in vivo tenogenesis

“…Given that tissue graft based therapies have failed to restore native tendon function, it is anticipated that the tissue-engineering arpeggio (scaffolds, cells, biologics alone or in combination) would provide a functional therapy in the years to come [1][2][3][4][5][6][7][8][9][10][11][12][13].…”

Adipose-Derived Mesenchymal Stem Cells Treated with Growth Differentiation Factor-5 Express Tendon-Specific Markers

“…27,28 Such combined tissue-engineered therapies also have significant potential in the bioengineering of tendon. 29 Preliminary data from our group have been promising, showing that GDF-5 treatment leads to increases of overall proliferation, total DNA, hydroxyproline (OHP), and glycosaminoglycan (GAG) expression of rat ADMSCs. 30,31 However, the effect of GDF-5 on the tendonogenic differentiation of ADMSCs has not yet been fully investigated.…”