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COLUMNS
Harnessing Self-Renewing Cells for Treatment of Cartilage Damage
Osteoarthritis is an extremely common condition – causing pain in joints during walking, standing, and other activities – that afflicts many, especially the elderly; researchers are working on using mesenchymal stem cells for more effective cartilage repair to prevent the onset or progression of osteoarthritis.
by Dr Yang Zheng and Prof Jongyoon Han

In the United States, around 32.5 million adults are diagnosed with cartilage degeneration, more commonly known as osteoarthritis. In Singapore, osteoarthritis affects up to 1 in 10 adults and 1 in 5 seniors.1 Although many cartilage repair techniques have progressed over the past few decades, current surgical treatments are unable to prevent the progressive degeneration of articular cartilage. Cell therapy has, on the other hand, shown potential in helping to regenerate cartilage tissue, particularly through the use of stem cells, but still faces challenges in terms of the consistency of outcome needed for effective clinical use.

Research institutes based in Singapore – such as the Singapore-MIT Alliance for Research and Technology (SMART) – have been working on methods of improving the manufacturing of mesenchymal stem cells (MSCs) for use in cell-based therapy for cartilage damage and paving the way toward regulatory approval and clinical use.

What is Osteoarthritis?

Osteoarthritis is an extremely common degenerative disease of the cartilage that is perpetuated by local inflammation that can cause pain and disability, especially in weight-bearing joints. It is often found among individuals aged 40 years and above, those who are obese, as well as athletes who participate in high-impact sports with a history of cartilage injury. The disease poses an economic burden in terms of lost productivity, as well as a significant loss in overall quality of life.

Articular cartilage is a glass-like white tissue at the end of a long bone, which acts as an efficient cushion that provides the smooth function of the joint for movement and weight-bearing. Unlike skin or bone, the lack of blood vessels in an articular cartilage hinders its ability to heal. If an injury to the cartilage persists, changes in weight-bearing and the release of inflammatory mediators in the joint cavity can result in cumulative cartilage degeneration and predispose the patient to develop osteoarthritis.

Existing Osteoarthritis Treatments

Currently, the main forms of osteoarthritis treatments can be categorised into pharmacological therapy and surgery. Pharmacological drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, can relieve pain but do little to reverse the degenerative condition. Although cartilage repair techniques have evolved over the past three decades, none of these treatments can prevent the affected articular cartilage from progressive destruction. Viscosupplementation – the process of injecting hyaluronic acid into the joint – may improve pain and function of the knee joint, but has not been able to significantly improve clinical outcomes. It is therefore important to effectively repair damaged cartilage through early intervention to prevent the onset of osteoarthritis. Surgical treatments to repair damaged cartilage, such as debridement, or microfracture procedures that allow access to bone marrow, however, do not perform better than placebo,2,3 or tend to generate functionally weak tissue.

Cell Therapy Using Stem Cells

Cell therapy for cartilage repair using patient tissue-derived cartilage cells (chondrocytes), also termed autologous chondrocyte implantation (ACI), has shown promising outcomes in the regeneration of functional, competent tissue. However, ACI has significant disadvantages. It requires two separate surgeries, and because the cells are derived from the patient, challenges—such as the ability to obtain sufficient cell numbers from the patient’s own joint, especially in those that have already suffered damage or deterioration such as that derived from an ageing joint—may result in chondrocytes of poor quality for therapy.

Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the body (not just limited to a single tissue source). They have self-renewing capabilities and can develop into various types of specialised cells, including bone, fat, and cartilage cells, allowing the regeneration of functionally competent tissues. MSCs are also known for their immune-modulatory properties, releasing molecules that act as cellular communicators to elicit biological responses in surrounding cells and establish a regenerative microenvironment conducive to tissue repair.

Furthermore, they are immune privileged, such that they are able to evade targeting by the host immune system and therefore present a lower risk of tissue rejection even when a patient receives cells from other donors. These properties make MSCs a promising cell source of choice for cartilage. The application of cells derived from donors to patients, also termed allogeneic cell therapy, has several important benefits.

Firstly, there is a greater supply of cells for several patients, which translates into the availability of therapies for more patients, “on-demand”, and better cost efficiency.

Secondly, in elderly patients where healthy stem cells may be low in numbers or quality, allogeneic MSC therapy provides a ready source of healthy stem cells for therapeutic use.

Several clinical studies have evaluated MSC application for cartilage repair, including a pioneering trial by National University Hospital in Singapore. Long-term (10 years) follow-up indicates improved clinical outcomes with treatment using patient-derived MSCs that are on par with ACI.4

Remaining Challenges of Therapeutic Application of MSCs

Despite the increasing clinical exploration of the use of MSCs, the outcomes have been plagued by substantial variability and inconsistency.

A large plausible contributor to the variable and unpredictable outcomes is their heterogeneous nature. Firstly, MSCs obtained from various parts of the body differ in their biological characteristics. Secondly, the quality and level of function of the MSCs vary according to the age and health conditions of an individual. Thirdly, even in an individual, MSCs derived from a single site vary in terms of physical and biochemical properties and therefore are not functionally homogeneous.

Of the most researched and clinically applied sources of MSCs, those derived from bone marrow comprise only 0.001 to 0.01 per cent of the cells in the bone marrow taken from part of the largest bone in the hip (iliac crest). The small amount of isolated MSCs has to undergo extensive laboratory culturing and expansion to generate enough quantity (5 to 20 million cells) for patient use to treat an average-sized cartilage lesion. When grown in the laboratory, cells become more heterogeneous in terms of their genetic, biological, and biophysical properties as they are easily perpetuated by slight changes in propagation procedures. A single donor MSC, with variable cell appearance, sizes, and phenotypes has wildly different functionality, which critically affects their overall ability to form cartilage cells.

Managing the Heterogeneity of MSCs for Enhanced Therapeutic Efficacy

Researchers at several research institutes and university-based laboratories in Singapore have recognised the importance of managing the heterogeneity of MSCs to improve the efficacy of stem-cell-based cartilage regeneration.

Collaboration between SMART’s Critical Analytics for Manufacturing Personalized-Medicine (CAMP) Interdisciplinary Research Group and the National University of Singapore Tissue Engineering Programme’s Stem Cell & Cartilage Research team aims to develop new ways to reduce MSC heterogeneity during cell propagation in the laboratory. Instead of the conventional two-dimensional static culture, various cell expansion platforms, such as an active three-dimensional bioreactor culture, or the supplementation of specific chemicals to spur cell growth, are being explored.

One novel approach emphasises identifying and enriching certain cell subpopulations with desirable functionality for more efficacious cartilage repair from the propagated heterogenic MSCs. By being passed through a specifically designed palm-size spiral micro-channel device developed in the laboratory of Jongyoon Han, CAMP Principal Investigator and professor at MIT, MSCs are separated into subpopulations of different cell sizes.5,6 Large quantities of MSC can be processed without any additional treatment using chemicals. Laboratory evaluation and proof-of-concept studies on animals have identified and validated the superior cartilage regenerative quality of a particular subpopulation of a defined size range.

This novel, high-throughput and minimally manipulative approach to isolating functionally optimal MSCs that are consistent in size and function could be easily adopted as a pre-operative procedure for cartilage regeneration therapy. The availability of such functionally consistent MSCs will make the application of such therapy for cartilage repair more attractive for clinicians, with a better promise of successful treatment that will allow patients a quicker return to normal activity.

Cumulative research efforts have placed Singapore at the forefront of MSC-based cartilage regeneration therapy, allowing for better and more accurate prediction of treatment outcomes. Moving ahead, the concerted efforts of researchers, clinicians, and industry players will provide a rational pathway to regulatory approval of MSC manufacturing and deployment for cartilage treatment and other therapeutic applications.

References:

  1. Leung YY, Pua YH, Thumboo J. A Perspective on Osteoarthritis Research in Singapore. Proceedings of Singapore Healthcare. 2013;22(1): 31-39.
  2. Karuppal R. Current concepts in the articular cartilage repair and regeneration, J. Orthop. 2017;14 (2):A1–A3.
  3. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am. J. Sports Med. 2009;37(10):2053—63.
  4. Teo AQA, Wong KL, Shen L, Lim JY, Toh WS, Lee EH, Hui JHP. Equivalent 10-Year Outcomes After Implantation of Autologous Bone Marrow-Derived Mesenchymal Stem Cells Versus Autologous Chondrocyte Implantation for Chondral Defects of the Knee. Am J Sports Med. 2019;47(12):2881-7.
  5. Yin L, Wu Y, Yang Z, Tee CA, Denslin V, Lai Z, Lim CT, Lee EH, Han J. Microfluidic label-free selection of mesenchymal stem cell subpopulation during culture expansion extends the chondrogenic potential in vitro. Lab Chip. 2018;18(6):878-89.
  6. Yin L, Yang Z, Wu Y, Denslin V, Yu CC, Tee CA, Lim CT, Han J, Lee EH. Label-free separation of mesenchymal stem cell subpopulations with distinct differentiation potencies and paracrine effects. Biomaterials. 2020;240:119881.
About the Authors
Dr Yang Zheng is Council Member and Crosscut Captain of the Critical Analytics for Manufacturing Personalized-Medicine (CAMP) Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), MIT’s Research Enterprise in Singapore.

She is also a Principal Investigator at the National University of Singapore (NUS) Tissue Engineering Programme under NUS’ Life Sciences Institute, and Senior Research Fellow at the Department of Orthopaedic Surgery at NUS Yong Loo Lin School of Medicine.

Prof Jongyoon Han is a Principal Investigator (PI) at the Critical Analytics for Manufacturing Personalized-Medicine (CAMP) Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), MIT’s Research Enterprise in Singapore.

He is also currently a professor at MIT’s Department of Electrical Engineering and Computer Science and the Department of Biological Engineering, and is the lead PI for MIT’s engagement in the National Institute for Innovation in Manufacturing Biopharmaceuticals.

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