Osteoarthritis (OA) is a debilitating degenerative disease that afflicts an estimated 27 million Americans age 25 and older. This disease leads to the progressive degradation of the articular layers of diarthrodial joints, significantly compromising the main function of cartilage as a load bearing material, leading to pain and limiting activities of daily living. Cartilage functional tissue engineering is a highly promising technology that aims to provide a biological replacement to worn articular layers, as a modality that considerably expands the limited options in the treatment of this disease. Though cartilage degeneration is occasionally limited to small focal areas within articular layers, OA generally becomes symptomatic when degradation has spread over much greater surface areas (such as greater than 25 percent of the articular layer). Unfortunately, functional tissue engineering of large cartilage constructs is significantly constrained by the balance of nutrient transport and consumption. Several studies have shown that matrix deposition and elaboration of functional properties preferentially occurs near the periphery of constructs, where nutrient supply from the surrounding culture medium is most abundant, whereas cells in the interior receive less nutrients and produce less matrix, with poorer functional properties. In this application, an engineering solution is proposed for the technical challenge of supplying plentiful nutrients for large engineered cartilage constructs by optimizing the number and spacing of narrow channels through the full thickness of construct layers, thus recapitulating the nutrient supply provided by cartilage canals during early development. The placement of channels in constructs of various dimensions must be optimized to balance competing needs: Increasing the channel density would logically increase the total nutrient supply, spreading it more evenly across the entire construct. However, an elevated channel density may effectively decrease the cell density and increase the pathways for loss of synthesized matrix products before they bind to the extracellular matrix. This type of optimization analysis, where competing needs must be balanced, is very well suited for an engineering approach that accounts for the dominant mechanisms regulating tissue growth. The development of this engineering technology will proceed through four specific aims: (1) Implement solute diffusion/binding/consumption and tissue growth equations from existing models into custom-written finite element software for the analysis of tissue engineered constructs. (2) Experimentally characterize the parameters needed for modeling nutrient supply and matrix growth in engineered cartilage. (3) Use these computational tools and experimental data to perform the optimization analysis for channel placement in large cylindrical and patella-shaped articular layer constructs. (4) Culture large constructs using theoretically optimal (N) and sub-optimal (N/2 and 2N) number of channels, as well as channel-free controls;compare matrix deposition and functional properties to test that N is the optimal value;refine model if necessary.

Public Health Relevance

Osteoarthritis (OA) of the knee and hip is most often associated with loss of cartilage over relatively large regions of the articular layers. OA patients have limited treatment options: Early interventions mostly address pain management, whereas advanced stages of the disease are generally treated with joint replacement, a treatment constrained by the life expectancy of patients in relation to the survival rate of implants. Cartilage tissue engineering offers an opportunity to provide a biological implant as an intermediate treatment modality that follows conservative pain management but postpones (or possibly eliminates the need for) joint replacement. The technology proposed in this application will facilitate engineering of large cartilage tissue constructs needed to resurface defects in OA joints.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR060361-01
Application #
8025654
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2010-09-20
Project End
2015-08-31
Budget Start
2010-09-20
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$341,587
Indirect Cost
Name
Columbia University (N.Y.)
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
O'Connell, Grace D; Tan, Andrea R; Cui, Victoria et al. (2017) Human chondrocyte migration behaviour to guide the development of engineered cartilage. J Tissue Eng Regen Med 11:877-886
Silverstein, Amy M; Stoker, Aaron M; Ateshian, Gerard A et al. (2017) Transient expression of the diseased phenotype of osteoarthritic chondrocytes in engineered cartilage. J Orthop Res 35:829-836
Nims, Robert J; Cigan, Alexander D; Durney, Krista M et al. (2017) * Constrained Cage Culture Improves Engineered Cartilage Functional Properties by Enhancing Collagen Network Stability. Tissue Eng Part A 23:847-858
Silverstein, A M; Stefani, R M; Sobczak, E et al. (2017) Toward understanding the role of cartilage particulates in synovial inflammation. Osteoarthritis Cartilage 25:1353-1361
Tan, Andrea R; Hung, Clark T (2017) Concise Review: Mesenchymal Stem Cells for Functional Cartilage Tissue Engineering: Taking Cues from Chondrocyte-Based Constructs. Stem Cells Transl Med 6:1295-1303
Bernhard, Jonathan C; Vunjak-Novakovic, Gordana (2016) Should we use cells, biomaterials, or tissue engineering for cartilage regeneration? Stem Cell Res Ther 7:56
Nover, Adam B; Hou, Gary Y; Han, Yang et al. (2016) High intensity focused ultrasound as a tool for tissue engineering: Application to cartilage. Med Eng Phys 38:192-8
Cigan, Alexander D; Nims, Robert J; Vunjak-Novakovic, Gordana et al. (2016) Optimizing nutrient channel spacing and revisiting TGF-beta in large engineered cartilage constructs. J Biomech 49:2089-2094
Cigan, Alexander D; Roach, Brendan L; Nims, Robert J et al. (2016) High seeding density of human chondrocytes in agarose produces tissue-engineered cartilage approaching native mechanical and biochemical properties. J Biomech 49:1909-1917
Jones, Brian; Hung, Clark T; Ateshian, Gerard (2016) Biphasic Analysis of Cartilage Stresses in the Patellofemoral Joint. J Knee Surg 29:92-8

Showing the most recent 10 out of 36 publications