ABSTRACT
As cartilage has poor innate repair and regeneration capacity, therapies that can address early cartilage injury
and prevent further osteoarthritic deterioration would have a large clinical impact. Due to the ease of isolation
and multi-lineage differentiation potential of mesenchymal stromal cells (MSCs), methods that rely either on
matrix assisted mesenchymal-stromal-cell-implantation (MSCI) or microfracture (MF) have attracted clinical
attention. Currently, the functional outcomes of MSCI or MF, including approaches that deliver growth factors in
vivo, are characterized by biomechanically inferior fibrocartilage, and poor integration scores. Joint inflammation
has been identified to inhibit chondrogenesis of MSCs, thus contributing to the low efficacy of cartilage repair
outcomes. Critically, approaches that offer chondroprotection by the mitigating the catabolic effects of the pro-
inflammatory joint environment while promoting in situ chondrogenesis are required. To address the critical
challenge of improving functional-cartilage-repair outcomes, a non-invasive adjunct; continuous low-
intensity ultrasound (cLIUS) with recently published chondroinductive and chondroprotective properties
to demonstrate enhanced chondral repair for both MACI and MF procedures will be employed. The ability
of cLIUS to improve cartilage repair outcomes will be demonstrated via three specific aims: AIM 1: Demonstrate
cLIUS-induced chondrogenesis of MSCs in a pro-inflammatory environment. RNA-sequencing will be
employed to gather an in-depth transcriptomic profiling and underlying pathways that drive MSC chondrogenesis
under cLIUS in a pro-inflammatory environment. AIM 2: Develop a computationally validated and optimized
regimen of cLIUS therapy. Computational grids will be built from magnetic resonance images (MRIs) coupled
with a biphasic finite element model for wave propagation in the joints to determine the specific cLIUS regimen
for sheep joints. Models will be validated with acoustic propagation experiments in sheep-cadaver knee joints.
AIM 3: Demonstrate Improved Functional Outcomes of Cartilage Repair Under cLIUS. Demonstrate the
superior repair of critically sized chondral defects via MF and MSCI in the articular cartilage of sheep using an
optimized transdermal delivery of cLIUS and evaluate at six months. Analysis of regenerated cartilage will be
through histological, biomechanical and biochemical methods. Successful completion of this work is expected to
lead to the development of a cLIUS-based regimen and delivery system capable of generating a stable hyaline
cartilage phenotype via minimally invasive procedures, while advancing the fundamental understanding of MSC
preconditioning under cLIUS. This would, in turn, directly address the treatment of 46 million Americans who
suffer from OA at an estimated cost of $128 billion annually.