Fig. 39.1
Gross pathology 12 month follow-up after autologous chondrocyte transplantation in the Canine model. Level L3–L4 was transplanted, level L1–L2 received no treatment and displayed more scar tissue, L2–L3 was the control level with a normal intervertebral disk
Tissue analyses included light microscopy and immunohistochemistry for assessing BrdU content (Fig. 39.2) and collagen expression.
Fig. 39.2
Staining of paraffin sections of the regenerated intervertebral disk 6 months following cell transplantation. BrdU-containing chondrocytes were detected and stained by immunohistochemical procedures using DAB as the chromogen. Sections were counterstained by eosin. BrdU-positive cells are colored black. (a) Nucleus regenerates overview (25×); (b) BrdU-stained transplanted cells (200×); (c, d) single BrdU-stained transplanted chondrocytes, pericellular de novo synthesis of nucleus matrix (1,000×)
The canine study evaluated whether autologous disk cell transplantation might be an appropriate therapeutic treatment to repair disk damage and inhibit degeneration. In this context, several important observations emerged:
1.
Autologous disk cells were expanded in culture and returned to the disk by a minimally invasive procedure after 12 weeks. Under defined conditions, it was possible to assure phenotype and assess metabolic capacity of the cells prior to transplantation.
2.
Disk cells remained viable after transplantation as shown by BrdU incorporation and maintained a capacity for proliferation after transplantation as depicted by histology.
3.
Transplanted disk cells produced an extracellular matrix that contained components similar to normal intervertebral disk tissue. Positive evidence of proteoglycan content was supported by accepted histochemical staining techniques such as safranin O-fast green.
4.
Both Type II and Type I collagens were demonstrated in the regenerated intervertebral disk matrix by immunohistochemistry following chondrocyte transplantation.
5.
There was a statistically significant correlation between transplanting cells and retention of disk height that was demonstrated at longer intervals following transplantation.
Although a morphotypic nucleus pulposus was not generated, cells that could appropriately be considered disk cells were identified in the intervertebral disks that had received disk cell transplantation. The observed matrix to cell ratio suggested strongly that these cells were elaborating a cartilage-specific matrix that was appropriate with respect to both collagen and proteoglycan components. No evidence of necrotic change was present, nor were there any active signs of tissue vascularization. Absence of bone in the intervertebral space and the productive matrix synthesis suggested that active remodeling and expression were guided by the demands of the anatomy and that cell response after transplantation was dependent on both the phenotypic identity of the cells and the biomechanical cues of the anatomy.
Cell viability and their capacity for matrix synthesis were particularly encouraging outcomes of this study. In the light of a 12-week interval between disk tissue sampling and cell transplantation, cells were placed into an environment that had fundamentally changed in both composition and function. Under the provision of central delivery and pressurized containment, the transplanted cells were prepared for the environment of the nucleus pulposus. The high cell to volume ratio of the transplanted cells, the deformable nature of the regional anatomy, and the inherent capacity of the cells to respond to new loading regimens all supported the vitality of the transplant conditions.
Extracellular matrix change, biomechanical variation, altered morphology, and cell viability are acknowledged steps leading to intervertebral disk degeneration. In the process of invigorating the population of vital disk cells and achieving matrix transformation, a positive observation regarding the morphology of the disk was made. The ability to control cell conditions, potentially to imbue the cells with additional genetic capacity, and the availability of autologous tissue from diskectomy procedures make this technology both feasible and attractive.
39.3 EuroDisc Randomized Trial
After these positive and promising results, the EuroDisc Randomized Trial was initiated to embrace a representative patient group, examining not only the traumatic, less degenerative disk, but also to include patients with persistent symptoms that had not responded to conservative treatment and in whom a surgical treatment is considered.
Interventional surgery for disk herniation is one of the most widely used and effective treatments for back pain that emerges within the broad scope of disk degeneration. Successful removal of impinging tissue offers the individual patient substantial relief for associated pain. However, the reduction of tissue involved with the surgical procedure anatomically compromises the function of the affected disk and effects a load transfer to adjacent disks. Biological restoration with interventional cell therapy offers a potential for accentuating disk metabolism with an underlying intent to restore spine mechanics.
Patients who were to undergo surgical intervention at one level were eligible for participation in the trial; patients requiring treatment at more than one level were excluded from the study. Prior to their participation, all patients were advised of the potential risks and signed a letter of consent. No placebo group was committed to this study; each patient participating in the clinical trial was to undergo surgical treatment for their disk prolapse, and the prospective basis of cell transplantation separated the active treatment group from the control group. Patients were not blinded to their treatment. Randomization was done after the open microdiskectomy. Eligibility was limited to patients between 18 and 60 years of age, with a body mass index (BMI) below 28. Exclusion criteria for participating in the study included sclerotic changes, edema, Modic changes of Types II or III, and spondylolisthesis among other accepted criteria such as pregnancy, etc.
Operative procedures were performed as minimally invasive open sequestrectomies performed by an experienced neurosurgeon under general anesthesia. The harvested cells from the sequestered disk material were cultured by the Co.don AG Teltow/Germany under GMP conditions. More than five million living disk cells were included in the solution for transplantation.
A single puncture with a minimal caliber cannula was used to achieve a precise delivery with minimal trauma to the patient and to the anulus (Fig. 39.3). The technique was developed with respect to literature that has demonstrated a size-specific correlation between anular injury and disk degeneration. A simple, minimal invasive technique was necessary to reduce the wound site trauma and effectively support cell injection without further injury to the anulus. Cells were transplanted approximately 12 weeks following sequestrectomy to assure that the anulus has healed and will contain the cells. Using a pressure-volume test prior to the delivery of any chondrocytes, cells could be placed with the confidence that they would be retained at the site of delivery.
Fig. 39.3
Intraoperative setting. (a) Fluoroscopic-guided minimal invasive puncture of the intervertebral disk form the opposite side, (b) pressure-volume-test, (c) cell transplantation
One hundred and twelve patients have been enrolled in the EuroDisc Study; the primary criteria follow-up was intended to occur at 1 year, an interim analysis scheduled at 2 years, and the final analysis will be completed at 4 years. The primary clinical evaluation criterion was the Oswestry Low Back Pain Disability Questionnaire. Secondary criteria include the SF-36, Prolo Score [32], Quebec Back Pain Disability Scale, MRI, and X-ray evaluation. The use of the Oswestry disability questionnaire in clinical trials is recommended by the German Orthopedic Society (DGOT), demonstrating acceptable test quality and satisfactory test-retest reliability. The Quebec Back Pain Disability Scale, another self-rating scale, was professionally developed using factor analysis comprising high internal consistency, high item discriminability, and high test-retest reliability. Finally, the SF-36, an often used scale to assess patients’ general condition and quality of life, and a VAS will be used to standardize measureable pain.
The interim analysis, made by a cut in January of 2006 to assess whether intervention correlated with positive clinical outcomes, forms the basis for this report. Within the analysis, successive 3-month, 6-month, 12-month, and 24-month assessments are stratified within the continuum of the study. The information within this study allows a broad interpretation of the general progress made over 2 years following a clinical intercession with autologous disk cells. Interim analysis was performed on the first 28 patients who reached 24-months follow-up with regard to autologous disk cell transplantation (ADCT). These first 28 patients were randomized in three different centers.
For descriptive analysis of efficacy, the total sum score as well as the disability index of the Oswestry Low Back Pain Disability Questionnaire (OPDQ) and the total sum score of the Quebec Back-Pain Disability Scale (QBPD) were taken into account from the initial presurgical presentation through the 2-year follow-up. The outcomes are depicted in Table 39.1. Based on the mean total sum score as well as the disability index of the OPDQ, differences in initial presentations between the control group and those receiving autologous cells were not minimal. Surgery as an intervention was a positive experience and, as expected, substantially reduced the patient’s disability and pain. The trend in reduction of the total sum score continued to decrease in the patients whose treatment was supplemented by cell transplantation, while the control group did not sustain continual improvement. Two years following the therapeutic intervention with cells, both the total sum score and the disability index of the OPDQ were lower in the ADCT group compared with the control.
Table 39.1
Total sumscore and disability index of the OPDQ based on patients who had been followed for 2 years after autologous disk chondrocyte transplantation
Total sumscore | |||||||||
|---|---|---|---|---|---|---|---|---|---|
N | Mean | SD | Min | Lower quartile | Median | Upper quartile | Max | ||
Visit -1 | ADCT | 12 | 28.42 | 9.30 | 13.00 | 20.00 | 29.50 | 36.00 | 45.00 |
Control | 16 | 26.88 | 9.99 | 14.00 | 18.00 | 25.50 | 34.00 | 46.00 | |
Visit 0.5 | ADCT | 12 | 8.00 | 6.89 | 0.00 | 2.50 | 7.50 | 12.50 | 24.00 |
Control | 15 | 8.40 | 4.69 | 1.00 | 4.00 | 9.00 | 13.00 | 15.00 | |
Visit 1 | ADCT | 11 | 6.73 | 8.56 | 0.00 | 0.00 | 5.00 | 12.00 | 28.00 |
Control | 14 | 7.14 | 6.36 | 0.00 | 1.00 | 5.50 | 13.00 | 19.00 | |
Visit 2 | ADCT | 10 | 9.10 | 10.72 | 0.00 | 1.00 | 6.50 | 12.00 | 35.00 |
Control | 14 | 7.79 | 7.42 | 0.00 | 2.00 | 6.50 | 12.00 | 26.00 | |
Visit 3 | ADCT | 11 | 7.82 | 8.46 | 0.00 | 2.00 | 4.00 | 15.00 | 25.00 |
Control | 14 | 7.07 | 5.94 | 0.00 | 1.00 | 7.00 | 12.00 | 19.00 | |
Visit 4 | ADCT | 12 | 6.00 | 8.89 | 0.00 | 0.00 | 2.00 | 8.50 | 29.00 |
Control | 16 | 7.56 | 6.52 | 0.00 | 2.50 | 6.00 | 13.00 | 19.00 | |
Disability index (%) | |||||||||
Visit -1 | ADCT | 12 | 56.83 | 18.60 | 26.00 | 40.00 | 59.00 | 72.00 | 90.00 |
Control | 16 | 53.75 | 19.97 | 28.00 | 36.00 | 51.00 | 68.00 | 92.00 | |
Visit 0.5 | ADCT | 12 | 16.06 | 13.73 | 0.00 | 5.33 | 15.00 | 25.00 | 48.00 |
Control | 15 | 16.80 | 9.37 | 2.00 | 8.00 | 18.00 | 26.00 | 30.00 | |
Visit 1 | ADCT | 11 | 13.45 | 17.11 | 0.00 | 0.00 | 10.00 | 24.00 | 56.00 |
Control | 14 | 14.29 | 12.72 | 0.00 | 2.00 | 11.00 | 26.00 | 38.00 | |
Visit 2 | ADCT | 10 | 18.64 | 21.53 | 0.00 | 2.00 | 13.89 | 26.67 | 70.00 |
Control | 14 | 15.62 | 14.80 | 0.00 | 4.44 | 13.00 | 24.00 | 52.00 | |
Visit 3 | ADCT | 11 | 15.64 | 16.92 | 0.00 | 4.00 | 8.00 | 30.00 | 50.00 |
Control | 14 | 14.14 | 11.88 | 0.00 | 2.00 | 14.00 | 24.00 | 38.00 | |
Visit 4 | ADCT | 12 | 12.00 | 17.79 | 0.00 | 0.00 | 4.00 | 17.00 | 58.00 |
Control | 16 | 15.19 | 12.99 | 0.00 | 5.50 | 12.00 | 26.00 | 38.00 | |
Descriptive analyses of the mean total sum score of the QBPD prior to sequestrectomy, prior to ADCT/control, and 3 months after ADCT/control demonstrated a decrease in mean and median sum scores in both groups. Although the mean and median values for both the ADCT and the control group decreased between 1 and 2 years, the assessments for the ADCT group were clearly lower (Table 39.2). Patient global assessment of pain demonstrated some fluctuation although both groups received substantial relief from the surgical intervention. However, as patients were tracked over the course of the 2-year follow-up, changes emerged that suggest that the ADCT-treated patients have a lower pain scores (Table 39.3).
Table 39.2
Total sumscore of the QBPD based on patients with at least 2 years follow-up after autologous disk chondrocyte transplantation
Total sumscore | |||||||||
|---|---|---|---|---|---|---|---|---|---|
N | Mean | SD | Min | Lower quartile | Median | Upper quartile | Max | ||
Visit -1 | ADCT | 12 | 45.08 | 17.60 | 23.00 | 31.50 | 42.00 | 55.00 | 82.00 |
Control | 16 | 49.69 | 18.69 | 21.00 | 34.00 | 45.00 | 65.00 | 81.00 | |
Visit 0.5 | ADCT | 12 | 14.75 | 16.07 | 0.00 | 4.50 | 8.50 | 17.50 | 50.00 |
Control | 15 | 18.27 | 11.04 | 1.00 | 6.00 | 19.00 | 25.00 | 38.00 | |
Visit 1 | ADCT | 11 | 10.64 | 16.05 | 0.00 | 1.00 | 4.00 | 15.00
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