Abstract

Emerging stem cell-based tissue engineering therapies that provide a biological solution to cartilage degeneration are considered advantageous over existing pharmacological or surgical approaches. While mesenchymal stem cells (MSCs) deriving from adult tissues such as bone marrow (BM) or fat are the most commonly used stem cell type in studies to date, the cells have several inherent properties that limit their potential for use in cartilage tissue engineering. We have recently demonstrated that cell reprogramming technology is able to transform a patient's own peripheral blood mononuclear cells into induced pluripotent stem cells (iPSCs) as a robust MSC source for tissue engineering. The use of iPSC-derived MSCs provides an opportunity for the development of personalized medicine for disease treatment. The objective of this proposed study is to develop an effective tissue engineering therapy for treatment of cartilage lesions caused by injuries or diseases, such as osteoarthritis (OA). We will explore the potential of using iPSC-derived MSCs to generate engineered cartilage in vitro and implanting the engineered cartilage for cartilage repair in vivo. To achieve the aim, we propose to establish working iPSC-derived MSC lines by reprogramming peripheral blood mononuclear cells harvested from human OA patients or sheep into iPSCs, and then deriving MSCs from the iPSCs. We will then culture iPSC-derived MSCs in functional nanofibrous scaffolds capable of preserving and releasing chondrogenic growth factors in a controllable fashion to generate cartilage. Cartilage generated from autologous sheep iPSC- or BM-derived MSCs, or xenogeneic human iPSC- derived MSCs will be used to repair cartilage in a sheep model. Comparison of these different groups with acellular scaffolds or a clinically relevant cartilage repair control, microfracture, will demonstrate the capability o different stem cell-based, engineered cartilage implants for the repair of cartilage defects. This project is innovative because we will apply transgene-free iPSC, nanofiber, controlled release and bioreactor technologies to enhance MSC chondrogenesis, and cartilage generation and repair in a large animal model to demonstrate the potential of our unique approach for clinical translation.

Public Health Relevance

Osteoarthritis (OA) is one of the leading health problems in the United States. According to the data from the Third National Health and Nutrition Examination Survey, OA affects nearly 21% of adults in the United States aged 35 years and older. The National Arthritis Data Workshop has estimated that 27 million adults in the U.S. experience clinical OA. Surgical procedures such as joint arthroplasty using metallic and plastic implants can help reduce pain and regain the anatomic structure and function of joints. However, the risk of infection and the challenge of compromised biocompatibility resulting from polyethylene wear sometimes lead to early failure of implants, which doesn't make joint arthroplasty a necessarily viable option for young or middle-aged patients who may need multiple surgeries over their lifetime to revise or replace failed implants. Emerging stem cell-based therapies providing a biological solution for the treatment of OA are considered advantageous compared to existing pharmacological or surgical approaches. We propose to utilize cell reprogramming technology to produce patient-specific induced pluripotent stem cells (iPSCs), and then use the iPSCs to generate functional cartilage in vitro for cartilage repair in a sheep model. This proof-of-concept study will test the feasibility of patient-specific stem cells fr the production of autologous cartilage implants for OA treatment, as validation of personalized medicine for clinical applications.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR064803-03
Application #
9320991
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2015-08-01
Project End
2020-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715