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 #
2R01EB008722-05A1
Application #
8690227
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Hunziker, Rosemarie
Project Start
2008-07-01
Project End
2018-03-31
Budget Start
2014-05-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$350,022
Indirect Cost
$125,022
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Farrell, M J; Shin, J I; Smith, L J et al. (2015) Functional consequences of glucose and oxygen deprivation onĀ engineered mesenchymal stem cell-based cartilage constructs. Osteoarthritis Cartilage 23:134-42
Fisher, Matthew B; Henning, Elizabeth A; Soegaard, Nicole B et al. (2014) Maximizing cartilage formation and integration via a trajectory-based tissue engineering approach. Biomaterials 35:2140-8
Mohanraj, Bhavana; Hou, Chieh; Meloni, Gregory R et al. (2014) A high throughput mechanical screening device for cartilage tissue engineering. J Biomech 47:2130-6
Farrell, Megan J; Fisher, Matthew B; Huang, Alice H et al. (2014) Functional properties of bone marrow-derived MSC-based engineered cartilage are unstable with very long-term in vitro culture. J Biomech 47:2173-82
Fisher, Matthew B; Mauck, Robert L (2013) Tissue engineering and regenerative medicine: recent innovations and the transition to translation. Tissue Eng Part B Rev 19:1-13
Bian, Liming; Hou, Chieh; Tous, Elena et al. (2013) The influence of hyaluronic acid hydrogel crosslinking density and macromolecular diffusivity on human MSC chondrogenesis and hypertrophy. Biomaterials 34:413-21
Bian, Liming; Guvendiren, Murat; Mauck, Robert L et al. (2013) Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis. Proc Natl Acad Sci U S A 110:10117-22
Kim, Iris L; Khetan, Sudhir; Baker, Brendon M et al. (2013) Fibrous hyaluronic acid hydrogels that direct MSC chondrogenesis through mechanical and adhesive cues. Biomaterials 34:5571-80
Erickson, Isaac E; Kestle, Sydney R; Zellars, Kilief H et al. (2012) Improved cartilage repair via in vitro pre-maturation of MSC-seeded hyaluronic acid hydrogels. Biomed Mater 7:024110
Bian, Liming; Zhai, David Y; Zhang, Emily C et al. (2012) Dynamic compressive loading enhances cartilage matrix synthesis and distribution and suppresses hypertrophy in hMSC-laden hyaluronic acid hydrogels. Tissue Eng Part A 18:715-24

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