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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB008722-06
Application #
8841348
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Hunziker, Rosemarie
Project Start
2008-07-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
6
Fiscal Year
2015
Total Cost
$426,990
Indirect Cost
$153,826
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kwon, Mi Y; Vega, Sebastián L; Gramlich, William M et al. (2018) Dose and Timing of N-Cadherin Mimetic Peptides Regulate MSC Chondrogenesis within Hydrogels. Adv Healthc Mater 7:e1701199
Vega, Sebastián L; Kwon, Mi Y; Song, Kwang Hoon et al. (2018) Combinatorial hydrogels with biochemical gradients for screening 3D cellular microenvironments. Nat Commun 9:614
Yousefi, Farzad; Kim, Minwook; Nahri, Syeda Yusra et al. (2018) Near-Infrared Spectroscopy Predicts Compositional and Mechanical Properties of Hyaluronic Acid-Based Engineered Cartilage Constructs. Tissue Eng Part A 24:106-116
Loebel, Claudia; Burdick, Jason A (2018) Engineering Stem and Stromal Cell Therapies for Musculoskeletal Tissue Repair. Cell Stem Cell 22:325-339
Heo, Su-Jin; Szczesny, Spencer E; Kim, Dong Hwa et al. (2018) Expansion of mesenchymal stem cells on electrospun scaffolds maintains stemness, mechano-responsivity, and differentiation potential. J Orthop Res 36:808-815
Martinez, Jerahme R; Grindel, Brian J; Hubka, Kelsea M et al. (2018) Perlecan/HSPG2: Signaling role of domain IV in chondrocyte clustering with implications for Schwartz-Jampel Syndrome. J Cell Biochem :
Sala, Renata L; Kwon, Mi Y; Kim, Minwook et al. (2017) * Thermosensitive Poly(N-vinylcaprolactam) Injectable Hydrogels for Cartilage Tissue Engineering. Tissue Eng Part A 23:935-945
McLeod, C M; Mauck, R L (2017) On the origin and impact of mesenchymal stem cell heterogeneity: new insights and emerging tools for single cell analysis. Eur Cell Mater 34:217-231
Meloni, Gregory R; Fisher, Matthew B; Stoeckl, Brendan D et al. (2017) Biphasic Finite Element Modeling Reconciles Mechanical Properties of Tissue-Engineered Cartilage Constructs Across Testing Platforms. Tissue Eng Part A 23:663-674
Vega, S L; Kwon, M Y; Burdick, J A (2017) Recent advances in hydrogels for cartilage tissue engineering. Eur Cell Mater 33:59-75

Showing the most recent 10 out of 51 publications