Differences in Interleukin-1 Response Between Engineered and Native Cartilage
Differences in Interleukin-1 Response Between Engineered and Native Cartilage
E. Lima et al. Tissue Engineering: Part A. Vol. 14(10):2008.
(link to pdf of summary)
The goal of cartilage tissue engineering is to replace degenerated cartilage with engineered cartilage tissue that has similar physical characteristics. Although fragile at formation, the engineered tissue matures over time and forms its own extracellular matrix that provides strength and protection. Clinicians choose whether to implant immature engineered tissue and allow it to mature in vivo or mature engineered tissue in vitro before implanting it.
The authors of this article hypothesized that in vitro maturation would provide better cartilage implants because the cartilage would have developed better protection against the harsh chemo-mechanical environment found in a diseased joint. Diseased joints usually have chronic inflammation, and so proinflammatory cytokines, such as Interleukin-1α (IL-1α) are present, which increase the catabolic rate of cartilage in vivo. To test their hypothesis, the authors explored the response of engineered cartilage versus native cartilage when exposed to inflammatory factor interleukin-1α in vitro.
The article consists of 3 studies. In all 3 studies, the authors compared the following physical characteristics to formulate their results: Young’s Modulus (E), Dynamic Modulus(G), GAG concentration, and Collagen concentration. The first 2 properties are mechanical properties, whereas the latter 2 are chemical properties.
In the first study, the authors compare native cartilage explants (bovine source) to engineered cartilage tissue. After 14 days of culture growth, IL-1a was introduced to some of the explants and engineered cartilage (considered immature at this time point). The samples that grew without IL-1a after day 14 served as controls. The properties of all the groups were analyzed at day 28. Compared to its control, the difference in all 4 properties of the explants was statistically insignificant, whereas the engineered tissue’s properties had degenerated significantly.
In the second study, the authors studied engineered cartilage at 3 different stages: at day 0 (immature), day 14 (immature) and day 28 (mature). These were the time points at which IL-1a was introduced to each culture. There was also a fourth control group that was cultured without IL-1a at any time point. After a total of 42 days, the properties of all groups were analyzed. The results showed that the two immature groups were significantly degenerated compared to the control group. The mature engineered tissue had no statistically significant differences in any of the 4 measured properties.
In the third study, the authors studied the growth of engineered cartilage and native explants in the presence of IL-1a as well as dexamethasone (dex), an anti-inflammatory chemical mediator that counters the effects of IL-1a. Engineered cartilage that had been grown in the presence of dex since the start had statistically insignificant properties compared to the control. Engineered cartilage that was grown in presence of both dex and IL-1a for 28 days didn’t different significantly either; even after removing dex (after day 28), the cartilage properties didn’t differ significantly. However, engineered cartilage that was grown in dex + IL-1a for only 14 days showed significant degradation once the dex was removed after day 14.
Results from all 3 studies signify that the response of engineered cartilage tissue to inflammatory factor IL-1a varies greatly depending on the level of maturity of the tissue culture and will significantly impact the clinical success of the engineered tissue after implantation. This study supports the idea that engineered cartilage constructs should be implanted when the tissue is functionally mature because the presence of an extracellular matrix will not only protect cells mechanically, but will also protect the cells from chemical degradation.
Significance:
Articular cartilage degeneration due to diseases such as osteoarthritis, rheumatoid arthritis, and other injuries lower the quality of life of a person significantly by making even the simplest of actions, such as walking or running, excruciatingly painful. These diseases are very common, especially in the older population. Currently, degenerated cartilage after repair surgeries is either replaced by a synthetic substitute (e.g. in total knee arthroscopy), or healthy cartilage (from external sources) is implanted in the hopes of promoting repair. Although both processes improve a patient’s quality of life, both of them have several flaws. Cartilage tissue engineering is a very important avenue of research as it provides a chance to improve the above mentioned methods of repairing or replacing degenerated cartilage. This paper in particular is quite useful as it provides a good insight into what kind of studies must be conducted to optimize the growth of cartilage tissue in vivo. The researchers reproduced some of the harsh in vivo chemical conditions that the cells would face in vitro and then analyzed different cultures to determine whether the maturity of the engineered tissue significantly alters its properties when placed in harsh chemical conditions. This paper has very practical conclusions that can improve the clinical success of engineered cartilage implants drastically.
3 comments:
Did the researchers suggest that it was the fully-grown extracellular matrix that protected the tissue, or did they think other factors were involved? And along those lines, were there any mentions of the substrate used by the engineered tissue making a difference in the "protective-ness" of the ECM?
I found this article very interesting, as I would have been more concerned that if an engineered tissue were allowed to fully mature in vitro, its mature form's properties may not be the same as those in the native cartilage because the in vitro environment lacks the same physical stresses/environment and may also lack some of the cell-cell signaling and interactions. Was there any discussion of how the tissue engineered cartilage actually fairs in vivo?
Matthew: They seem to be implying that there is a time period after which the tissue can be deemed 'mature' (as you said fully-grown) at which point the properties of the matrix are statistically better than immature tissue. As for substrate, the third study deals with adding a substrate (dex) to the growing culture.
Although it allows for better growth, this study doesn't really focus on comparing the substrate added culture to one that didn't have any substrate added directly, but you can actually make comparisons yourself by looking at the graphs (Figure 5).
Xiaogian: I agree that the properties will be different if the culture was grown in vivo, and the researchers are well aware of that. But from a tissue engineering perspective, their main concern is to improve the properties of externally designed tissues that can be implanted to replace native cartilage. This work just focuses on improving the properties of cartilage grown in vitro. They don't do implants, so they don't really do an in vivo study.
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