Articular cartilage lines the surfaces of joints and transmits the forces generated with loading. Due to limitations in the natural healing capacity of cartilage, and given the increasing incidence of osteoarthritis, there exists a growing demand for cell-based strategies for repair. Tissue engineering, and particularly those approaches based on autologous mesenchymal stem cells (MSCs), is evolving as a clinically relevant technique to promote cartilage regeneration. Yet, the formed tissue properties as well as the stability of phenotype and heterogeneous cellular response within constructs are concerns that currently limit translation of this technology. Our general approach to MSC-based cartilage repair addresses the differences observed between early rapid stages of cartilage formation and the gradual remodeling (maturation) that results in a tissue capable of adult function. This transformative process is driven by a multitude of temporal factors (chemical, mechanical, and soluble). Our progress during the ongoing grant has shown a role for matrix and cellular density, the timing of material degradation, introduction of soluble inductive factors, and mechanical loading (both compression and sliding contact) in guiding cartilage formation and maturation. Here, we build from these studies by introducing a developmentally relevant signal, namely cell-cell interactions through N-cadherin that are found during limb bud development, into our engineered hydrogel systems. In the first Aim, MSCs will be encapsulated in HA hydrogels modified with peptides that mimic the extracellular domain of N-cadherin, and the influence of peptide density on chondrogenesis and cartilage maturation will be investigated, in addition to the influence of the peptide on population heterogeneity and phenotypic stability. In the second Aim, the temporal presentation of the peptides will be investigated by introducing linkers that undergo cell-mediated proteolysis of the peptides from the HA hydrogels. The influence of the temporal peptide presentation on chondrogenesis, cartilage maturation, population heterogeneity, and phenotypic stability will be assessed as in the first Aim, in addition to the responsiveness to mechanical loading based on the acceleration of chondrogenesis. In the third Aim, N-cadherin peptide modified hydrogels, including both stable and transient presentation, will be investigated in a clinically-relevant load-bearing porcine defect model to assess the role of these interactions in an implanted hydrogel in cartilage defect repair.
These Aims were designed to allow the testing of our hypotheses that control over the MSC microenvironment, and inclusion of signals present during normal development that are both permissive and instructive for cartilage formation and maturation, will lead to the generation of constructs with properties akin to native tissue and improved repair.
This project develops a clinically-relevant approach to cartilage repair using MSC-laden hyaluronic acid hydrogels with controlled presentation of a molecule that regulates cell-cell interactions and is critical for normal cartilage development. The magnitude and timing of molecule presentation will be investigated towards the chondrogenesis of encapsulated MSCs and the maturation of a cartilage matrix, both in vitro as well as in a clinically relevant cartilage defect repair model. If successful, this approach would surmount a major hurdle in cartilage tissue engineering to provide a more developmentally relevant ECM with enhanced mechanical properties to support the intense loads found in the joint. This cartilage tissue engineering technique could aid in the treatment of millions of patients afflicted with debilitating cartilage loss and degeneration due to trauma or disease.
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|Heo, Su-Jin; Szczesny, Spencer E; Kim, Dong Hwa et al. (2017) Expansion of mesenchymal stem cells on electrospun scaffolds maintains stemness, mechano-responsivity, and differentiation potential. J Orthop Res :|
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|Cosgrove, Brian D; Mui, Keeley L; Driscoll, Tristan P et al. (2016) N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells. Nat Mater 15:1297-1306|
|Cote, Allison J; McLeod, Claire M; Farrell, Megan J et al. (2016) Single-cell differences in matrix gene expression do not predict matrix deposition. Nat Commun 7:10865|
|Caliari, Steven R; Vega, Sebastián L; Kwon, Michelle et al. (2016) Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments. Biomaterials 103:314-323|
|Saxena, Vishal; Kim, Minwook; Keah, Niobra M et al. (2016) Anatomic Mesenchymal Stem Cell-Based Engineered Cartilage Constructs for Biologic Total Joint Replacement. Tissue Eng Part A 22:386-95|
|Vega, Sebastián L; Kwon, Michelle; Mauck, Robert L et al. (2016) Single Cell Imaging to Probe Mesenchymal Stem Cell N-Cadherin Mediated Signaling within Hydrogels. Ann Biomed Eng 44:1921-30|
|McLeod, Claire M; Mauck, Robert L (2016) High fidelity visualization of cell-to-cell variation and temporal dynamics in nascent extracellular matrix formation. Sci Rep 6:38852|
|Fisher, Matthew B; Belkin, Nicole S; Milby, Andrew H et al. (2016) Effects of Mesenchymal Stem Cell and Growth Factor Delivery on Cartilage Repair in a Mini-Pig Model. Cartilage 7:174-84|
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