Regeneration of Intervertebral Disc Tissue by Resorbable Cell-Free Polyglycolic Acid-Based Implants in a Rabbit Model of Disc Degeneration
Alexander Abbushi, MD, Michaela Endres, PhD, Mario Cabraja, MD, Stefan Nicolas Kroppenstedt, MD, PhD, Ulrich Wilhelm Thomale, MD, Michael Sittinger, PhD, Aldemar Andres Hegewald, MD, Lars Morawietz, MD, Arne-Jorn Lemke, MD, PhD, Victor-Gotz Bansemer, MD, Christian Kaps, PhD, and Christian Woiciechowsky, MD, PhD
Intervertebral disc (IVD) degeneration is a major clinical concern regarding back pain and can be viewed be the height of the disc. The disc is composed of the anulus fibrosis (tough outer ring structure rich in collagen fibers) and the nucleus pulposus (a gelatinous inner core rich in proteoglycans). It is located between the vertebral bodies within the spine. During aging, the nucleus pulposus degenerates from the gel to a desiccated fibrocartilaginous structure similar to the anulus. Therefore, the repair of degenerated intervertebral discs can be achevied by stimulating the cells to produce matrix molecules and/or prevention of matrix degradation or cell death.
Model and Hypothesis
This study used an in vitro and a rabbit model to investigate the following: 1) show migration of IVD chondrocytes or mesenchymal stem cells in vivo using serum from whole blood, 2) reduce the loss of disc height after removing the nucleus by implanting the cell free polyglycolic acid (PGA) implants in vivo, and 3) induce the development of disc repair tissue by implanting the device in vivo.
They surgically removed the nucleus and some of the anulus of the L5/S1 disc on 12 live rabbits. Six of them received the PGA implant and the other six served as controls. The implant was a resorbable felt of pure PGA and was immersed in hyaluronic acid. They were then freeze dried for 16 hours and stored in a dessicator. Before implantation, the device was immersed in allogenic serum. The rabbits were then put down after 6 months and the operated discs were explanted and histologically investigated. MRI images and x-ray images were taken 1 week and 6 months after surgery. The MRI images measured the T2 weighted signal indicating water content and the x-rays were used to calculate disc heights. The explanted discs were cut into slices and stained with hematoxylin, eosin, and safranin O to asses tissue repair and regeneration.
After six months the MRI T2 signal increased by 45% for the PGA implant group where as the signal decreased by 11% in the control group. The x-ray data showed a narrowing of the discs for both groups but it was significantly less (27%) for the PGA group (see figure 2). The histological analysis showed regenerative effects and showed considerable amounts of repair for the PGA group (see figure 3). Chondrogenesis was occurring and the intercellular matrix showed characteristics of a proteoglycan rich cartilaginous tissue. The repair tissue was of regular cellularity and there were no signs of inflammations or malignant transformation. In the control group with no device, no regeneration or repair was detected.
Figure 2. Left: The disc height index (DHI) of sham operated and PGA-implanted animals taken 1 week and 6 months after surgery. The index decreased in both groups after 6 months. However, the decrease was significantly lower 27% (0.133 +/- 0.017 → 0.097 +/- 0.005) in the PGA implanted group compared with the shame group 39% (0.123 +/- 0.009 → 0.075 +/- 0.007 (*P < 0.05). Right: Representative lateral radiograph image of sham A, B and PGA implanted C, D animals. PGA-implanted animals showed a lower decrease in DHI compared with sham animal (see arrows). Furthermore, sham animals showed ventral osteophyte formation (*) demonstrating progression of the degenerative process.
Figure 3. Hematoxylin and eosin (A–C) and safranin O (D) staining of the central area of decalcified intervertebral discs 6 month after nucleotomy and implantation of PGA-constructs. The encircled small clusters of chondrocytes within a dense and homogeneous proteoglycan-rich matrix indicate tissue regeneration and repair tissue formation.
Significance:
Degenerated discs is the main cause of back pain and the lifetime prevalence is 75 – 80% of the population. Back pain is one of the major causes of disability and has a large socioeconomic impact. In this study, they have shown a way to slow disc degeneration and stimulate repair. The discs in the PGA group, increased in water content, were slower in the disc height decreasing, showed restoration of proteoglycans, showed chondrocytes producing extracellular matrix that contained components similar to IVDs, and there was no imflamation. These are huge results in the field of IVD regeneration. Future studies may lead to trying this device in humans and alleviating pain in many individuals and having a drastic effect on the socioeconomic problem with back pain.
4 comments:
Interesting! One question though: how does disc height correlate to the degenerative properties of IVD? You mentioned that a loss of disc height, although not in equal amounts, were observed in both the control and the group that received PGA. Does this mean that besides the regenerative effects of PGA, there was still some degeneration observed through loss of disc height? Or, is loss of disc height a natural process and was the 6 months post-surgery long enough for this natural loss of disc height to be observed?
It seems like the loss of disc height would affect the mechanical abilities of the spine to withstand physical loads from the body. However, I am not quite convinced that the disc height is a clear indicator of relative degeneration. From what I understand, it seems like the nucleus pulposus was removed in both the implanted and control discs. With one group of discs supported by the implant and the other group with a hole in the middle, won't the stress distributions and mechanical forces be significantly different between the groups thereby affecting the disc height after 6 months of different mechanical exposures?
@Denny
I don't think the purpose of the PGA implant was for mechanical, it seems like it should serve as a scaffold for cell regeneration and provides poor if any mechanical support.
However, you do raise an important point; for rabbits, their usual stance is four feet on the ground as opposed to humans who are upright. What would happen to the hollowed out discs in humans since this would seem to create greater stresses?
Are there any other method to increase the height of the disc without involving surgery, such as physically alleviating pressure from spine with a belt?
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