Stem Cell Constructs for Musculoskeletal Soft Tissue Engineering

Over 150,000 surgeries are done annually in the US alone to reconstruct the anterior cruciate ligament, the major joint stabilizer in the knee, and its meniscus -- these injuries could potentially benefit from tissue engineering approaches. Currently, autografts and allografts are used to reconstruct these tissues, but the resultant scar tissue is biomechanically and biologically inferior to the native tissue. IGERT Trainees in the M. Dunn (BME) laboratory will integrate human mesenchymal stem cells with collagen-based scaffolds for reconstruction of the ACL (Fig. 15 top) and meniscus (Fig. 15 mid). Following implantation of such materials, fibrous tissue is expected to grow into the scaffold around the collagen fibers (cf) (Fig. 15 bottom), but the rate and amount of ingrowth are inconsistent.

Fig. 15. Cell constructs for musculoskeletal regeneration.

To enhance ingrowth, scaffolds can be optimized for both mechanical properties and cellularity to be pre- seeded with cells and then implanted in the knee joint. The IGERT Trainees will seed these scaffolds with mesenchymal stem cells (MSCs) in efforts to enhance the rate, amount, and type of tissue ingrowth.  MSCs respond to biomechanical cues.  The hypothesis is that tensile loading (ACL) and compressive loading (meniscus) will cause differentiation of MSCs down the appropriate pathway (ligament or meniscus).  If this hypothesis is true, then it may be possible to regenerate the native structures by utilizing the pluripotential capacity of MSCs seeded on custom-designed scaffolds which are mechanically loaded in vitro and in the knee joint. Prior to surgical implantation, the MSC-seeded scaffolds, will be mechanically strained in vitro using a Flexcell Tissue Train System, causing cell differentiation (4) and matrix synthesis. IGERT faculty J. Kohn's lab (CCB) can provide synthetic biodegradable polymers that can be used to further strengthen the collagen fibers via collagen-polymer composites.  Trainees can collaborate with R. Hart's lab (BMB) and the Bionomics Center to perform gene expression profiling on the harvested scaffolds to evaluate their molecular-level functionality.