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Treatment of DDD/Disc Regeneration: Stem Cells, Chondrocytes
13.5 Challenges and Potential
Risks
The cell density in the human disc is extremely low with
between 2,000 and 5,000 cells/mm
Nevertheless, despite the low cell densities required for replacement of 1 mL of tissue, about 2 to 5 ×10
Therefore, due to the scarcity of MSCs in bone marrow or adipose tissue, cell proliferation and population expansion are still
required to obtain sufficient cells for implantation.
presents a significant challenge in not only har vesting but also
successfully expanding these cells. In addition, the optimal
number of cells for transplantation has not been established for
cell survival or for therapeutic effect.
All cells normally perform a limited number of cell dou-
blings when cultured in vitro, after which they become
90
"senescent."
Senescent cells not only cease to have the
ability to proliferate but also exhibit a distinct gene expression profile. These cells overexpress matrix metalloproteinases
(MMPs), catabolic factors, and inflammatory molecules, which
has been shown to affect tissue homeostasis.
important aspect to be considered in culture expansion of MSCs
for cell therapy. As discussed above, MSCs require extensive proliferation for use in cell replacement therapies if millions of
them are to be implanted. Several studies have indicated that,
even though MSCs are more resistant to senescence, repeated
proliferation can lead to a decreased differentiation capacity.
One method of obtaining sufficient cell numbers of MSCs for
clinical application is by density gradient centrifugation followed by ex vivo expansion. This process may cause a selection
for rapidly dividing cells, however, thereby increasing the risk
of genetic and epigenetic mutations. This can potentially lead to
the spontaneous transformation of MSCs, which has been suggested to be associated with tumor promotion.
Moreover, Miura and colleagues94also found that murine
bone marrow MSCs accumulated chromosomal abnormalities and were associated with both increased telomerase
activity and c-myc expression during long-term culturing.
Similarly, when the murine bone marrow–derived MSCs
were delivered systemically to immunocompromised mice
they generated fibrosa rcomas in multiple organs. In contrast,
the authors found a d ifferent behavior in human MSCs. They
discovered that human bone marrow–derived MSCs demonstrated no signs of immortalization with continuous culture
passages during expansion but d id exhibit cell senescence.
In a similar study in which human MSCs were populated to
greater than 30 doub lings, no karyotype abnormalities were
noted nor was telomerase activity present.
then transplanted the long-ter m cultured hum an MSCs into
mice and were able to continue to demonstrate the absence
of tumorigenesis.
However, other studies demonstrating in vitro malignan t
transformation of cultured human MSCs have challenged
these findings. One study noted that culture d human MSCs
exhibited a transformed phenotype and demonstrated chromosomal translocation and aneuploidy with increased telomerase activity. Moreover, when transplanted into
immunocompromised mice, the cultured human MSCs grew
solid tumors in multiple organs.
3
in the adult human NP.
6
of cells are needed.
91
This issue is an
89
95
The authors
96
These findings have not
89
This
92,93
been limited to bone marrow MSCs. ADSCs have also been
shown to exhibit spontaneous transformatio n and cell
97
immortalization.
When these cells were infused into
immunocompromised mice, tumor formation occurred in
almost all organs. However, in later experiments, the
88
authors were unable to confirm the in vitro transformation
of these ADSCs stem cells.
8998
Conversely, Bernardo and colleagues found that bone marrow
MSCs can be safely expanded in vitro and are not susceptible to
38
malignant transformation.
The authors investigated the susceptibility of bone marrow MSC transformation at different in
vitro culture points. The study included 10 healthy bone marrow donors. The isolated MSCs were propagated in vitro unt il
senescence, and the investigators found no chromosomal
abnormalities as well as no telomerase activity.
A further potential risk associated with MSCs is the promo tion of growth of established subclinical tumors within the
transplant patient. Bian et al showed that human MSCs in vivo
targeted established osteosarcomas and promoted tumor
99
growth as well as pulmonary metastasis.
In animal studies,
cotransplantation of cancer cells with MSCs promoted acceler-
100
ated growth of the cancer cells.
However, the authors note
that the studies that demonstrated the promotion of tumor
growth by the addition of MSCs utilized either immortalized or
modified MSC lines. In addition, 700 human subjects who
received autologous or third-party MSCs showed no major side
effects nor developed hematopoietic or solid tumors.
ever, the follow-up period of most of the clinical trials was relatively short (1 month to 6.8 years). The clinical manifestation
and occurrence of a tumor may certainly require longer
surveillance.
13.6 Conclusion
Although animal and human data on the regenerative poten tial of cell-based therapy for IDD are promising, questions
remain regarding the timing of treatment, optimal cell
source, cell pretreatment, and cell carrier. A main hurdle is
the limited understanding of IVD cell phenot ypes and their
modulation dur ing disc development, homeostasis, and disease. Curr ent knowledge indicates cellular injection therapy
is sa fe, although lo ng-term results are unknown. With the
increasing number of clinical trials, cell therapy for IVD
regeneration could bridge the gap between symptomatic
care and aggressive surgical interventions in some p atients
with IDD.
The solution to overcoming the obstacles that exist in developing cell therapies for IVD regeneration is to address each concern through focused research, both in the laboratory and in
the clinic. Well-controlled preclinical testing is needed to
address the long-term efficacy in using committed cells compared with adverse effects and concerns about the use of stem
cells. Consequently, the accumulation of well-designed and
case-controlled clinical trials for each question, in a stepwise
manner in concert with expert discussions and regulatory institutions, such as the US Food and Drug Administration (FDA),
will be crucial to surmounting the obstacles to stem cell therapy
in the treatment of IDD.
89
How-
117
Treatment of DDD/Disc Regeneration: Stem Cells, Chondrocytes
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Nucleus Replacement and Repair: Autologous Disc Chondrocyte Transplantation
14 Nucleus Replacement and Repair: Autologous Disc
Chondrocyte Transplantation
Christian Hohaus, Timothy Ganey, and Hans Jörg Meisel
Abstract
Intervertebral disc (IVD) degeneration is in 40% of younger individuals and in more than 90% of individuals older than 50 years
of age, a common disorder with a negative impact on life quality. Available treatment options, conservative as well as operative procedures, are limited and don’t treat the underlying
biological reason, IVD degeneration. Total regeneration of the
degenerated IVD is not currently considered a therapeutic
assurance. The goals of regenerative medicine at this time are
to prevent further progression of disc degeneration and its
associated symptoms.
What has been shown to date, and therefore available in limited geographies and jurisdictions, is that expanded and transplanted autologous cells are safe and appear to arrest if not
reverse degenerative disc disease (DDD) following treatment
for sequestrectomy. In our clinical trial with more than 140
patients, the largest number of patients with degenerated IVD
disease treated with cell transplantation under defined study
conditions, all patients have benefited from transplantation in
reduced back pain as one measure of an enhanced quality of life
and were able to return to work after transplantation. Moreover, the reduction in reherniation rate was more than 50% better than the control group.
The use of autologous chondrocytes requires the ex vivo
expansion of cells, adding burdens of cost, time, and regulation
that add to the intricacy of the procedure beyond the medical
interface. This limitation of the procedure could be avoided by
the use of a one-step procedure, using stem cells obtained from
autologous adipose tissue, with shows promising results in preclinical studies.
Cell transplantation appears to present an effective treatment
option in DDD. The transplantation of autologous disc cells is
currently the only biological treatment option with good clinical results under defined study conditions.
Keywords: autologous disc cell transplantation, cell therapy,
clinical study, degenerative disc disease, intervertebral disc, low
back pain
14.1 Introduction
Low back pain is extremely common, affecting nearly three
quarters of the population sometime in their life. More than
80% of the population will suffer from lumbar back pain once in
their lifetime.
months, in some patients chronic back or leg pain leads to longterm physical disability, and the reduced quality of life that it
imposes.
Disc anatomy would be expected to play a pivotal role and
correlate with the underlying pain, yet abnormal spine and disc
morphology including disc herniation has been described as a
normal component of an asymptomatic population.
1,2,3,4
Although most people recover within 3
5,6
IVD degeneration is influenced by multiple factors such as
7
age and genetic loading,
biomechanical forces,8and environ-
mental factors such as immobilization, trauma, and application
9
of nicotine.
Age-related diseases such as diabetes, arterial
hypertension, and complications attendant to vascular diseases
have been defined as relevant factors as well.
10
Accepting the vast prevalence of asy mptomatic disc
degeneration as noted, “normal” IVDs present an optimal
balance between anabolic and catabolic processes that are
regulated by anabolic growth factors, catabolic enzymes, and
11
pro-inflammatory cytokines.
Among the key anabolic
growth factors that have been noted are insulin-like growth
factor (IGF)-1, transforming growth factor (TGF)-β, and bone
12
morphogenetic proteins (BMPs).
Interleukin (IL)-1 and
TGF-α clearly are involved in catabolic activities in the
13
healthy I VD.
Catabolic processes contribute to changing
disc morphology and variations in matrix composition that
initially alters biochemical composition, and ultimately
result in the loss of proteoglycans a nd type II collagen. Following a restructu ring of the matrix, an increase in cell
death and decreasing nutrition further impose conditions
and predisposition to mechanobiological consequence and
precipitate a self-impo sing insult that furthers the degenerative process.
14,15,16,7,18
Therapeutic options for treating degene rative disc disease
(DDD) resulting from this knowledge have informed strategies including the substitution of growth factors, gene therapy tissue engineer ing, and cell transplantation. Some of
these efforts have met with suggestive success to the extent
that proteoglycan synthesis has been shown to increase in a
canine model af ter direct injection of recombinant TGF-β in
19
combination with epidermal growth factor.
Similarly, the
direct stimulation of cells with BMP-7 in rabbit IVDs
resulted in an increase in proteoglycan synthesis as well as
20,21,22
restoration of disc height.
The intradiscal application
of BMP-7 for regeneration of IVD degeneration in a natural
canine model, however, did not promote disc regeneration
but ins tead resulted in the formation of extradiscal bone.
A pilot clinical study combining matrix components and
growth factors that was directly injected into degenerated
discs stimulated IVD regeneration that was durable over the
24
course of a 12-month follow-up.
Despite the success
achieved, the concern for therapeutic support for such techniques seemed severely limited by the availability of viable
cells and the limitation in application only in early stages of
25
disc degeneration.
cells (MSCs) has also gained increasing attention,
Transplantation of mesenchymal stem
26,27,28,29
although critics of that strategy have weighed in on limitations of cell viability as concerning.
25
Given that disc herniation is thought to be an extension of
progressive disc degeneration that attends the normal aging
process, seeking an effective therapy that staves disc degeneration has been considered a logical attempt to reduce back pain.
Disc herniation is the most common reason for radicular
23
121
Nucleus Replacement and Repair: Autologous Disc Chondrocyte Transplantation
symptoms in the lumbar spine leading to an operative treatment. Herniated material from the degenerated disc has been
considered a potential donor for nucleus pulposus (NP) cells
and chondrocytes because of their extended viability.
ing and expanding these cells is not simple but is possible, and
following successful transplantation cells produce both type-II
collagen as well as appropriate proteoglycans.
of these expanded cultured cells would create an option to
enlarge the viable cell content in the degenerated disc and to
increase the necessary extracellular matrix (ECM).
31
30
Cultur-
Transplantation
14.2 Preclinical Study Using
Autologous Disc Cell
Transplantation for Nucleus
Regeneration in the Dog
This study31was performed to test the hypothesis that restoration of IVD morphology could be achieved by transplantation of
cultured autologous chondrocytes into the NP. The study
addressed the question of whether the introduction of cultured
autologous disc–derived cells would repair a damaged disc and
inhibit degenerative changes. The dogs were divided into two
basic groups; 4 animals receiving autologous cells containing
bromodeoxyuridine (BrdU) as a nuclear marker, the other 14
receiving autologous cells without a nuclear marker. Animals
were radiographed to establish a baseline for preexisting spine
pathology.
Lumbar IVDs at three levels (L1–2, L2–3, and L3–4) were
identified as study levels for the procedure and disc tissue was
collected. The sampled disc cells were expanded in culture
through several passages, producing approximately 6 million
cells with the goal of establishing a population of disc cells
capable of producing matrix and sustaining an expanded volume within the damaged disc. In this study, the L1–2 IVD had
tissue removed but did not receive chondrocyte transplantation, the L2–3 disc was approached but not violated and served
as a surgical control, and the L3–4 level had disc material
removed and received chondrocyte transplantation 12 weeks
later via left-side minimally invasive puncture of the IVD under
fluoroscopic imaging.
An important criterion for evaluating the success of cell transplantation in the disc repair procedure was identifying that
matrix regeneration was attributable to transplanted, cultured,
expanded disc cells rather than a result of inherent disc
capacity for self-repair. BrdU, an analog nucleotide of thymidine, was incorporated into the nucleus during deoxyribonucleic acid (DNA) synthesis and could later be identified by
immunohistochemical techniques. As such, it was possible to
analyze morphology in situ after repair, and delineate cells that
were transplanted from those already present in the host
tissue.
The animals were humanely euthanized 3, 6, 9, and 12
months following the cell transplantation. Immediately after
the dogs were killed, their lumbar spines were removed and
the tissue analyzed (▶ Fig. 14.1). Magnetic resonance imaging
(MRI) and X-ray analysis with coronal slices of the spinal column were performed to interpret disc height. Tissue analyses
Fig. 14.1 Gross pathology at 12-month follow-up after autologous
chondrocyte transplantation in the canine model. Level L3–4 was
transplanted, level L1–2 received no treatment and displayed more
scar tissue, and level L2–3 was the control level with a normal
intervertebral disc.
included light microscopy and immunohistochemistry for
assessing BrdU content (▶ Fig. 14.2) and collagen expression.
The results of this animal study were extremely promising for further clinical applications: Autologous disc cells
were expanded in culture and returned to the d isc 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. These transplanted disc cells remained viable
after transplantation as shown by BrdU incorporation and
maintained a capacity for proliferation after transplantation as depicted by histology. They produced an ECM that
contained components similar to nor mal IVD tissue. Both
type I and type II collagens were demonstrated in the
regenerated IVD matrix by immunohistochemistry following chondrocyte t ransplantation. And there was a statistically signif icant correlation between t ransplanting cells and
retention of disc height that was demonstrated at longer
intervals following transplantation.
31
122
Nucleus Replacement and Repair: Autologous Disc Chondrocyte Transplantation
14.3.2 Operative Treatment
Each patient participating in the clinical trial underwent surgical treatment for prolapsed disc. This was done as a minimally
invasive open sequestrectomy using a tubular retractor system
for minimal affection of the lumbar muscles. The use of an
operative microscope after opening the yellow ligament was
mandatory. This procedure was performed by an experienced
neurosurgeon with the patient under general anesthesia. Randomization was done after closure of the fascia thoracolumbalis, directly from the operating room to prevent surgical bias in
the evaluation of patients. The harvested cells from the sequestered disc material were cultured by co.Don AG (Teltow, Germany) under Good Manufacturing Practice (GMP) conditions.
Patients were not blinded to their treatment.
Fig. 14.2 Staining of paraffin sections of the regenerated intervertebral disc 6 months following cell transplantation. Bromodeoxyuridine
(BrdU)-containing chondrocytes were detected and stained by
immunohistochemical procedures using 3,3′-diaminobenzidine (DAB)
as the chromogen. Sections were counterstained by eosin. BrdUpositive cells are colored black. (a) Nucleus regenerate overview (25 ×).
(b) BrdU-stained transplanted cells (200 ×), (c,d) single BrdU-stained
transplanted chondrocytes, pericellular de novo synthesis of nucleus
matrix (1,000 ×).
14.3 Clinical Application of
Autologous Disc Chondrocyte
Transplantation in Degenerative
Disc Disease
After these positive and promising results demonstrating both
safety and efficacy, a randomized controlled study (the Euro
Disc Randomized Trial) was designed to embrace a representative patient group, examining not only the traumatic, less
degenerative disc, but also to include patients with persistent
symptoms that had not responded to conservative treatment
where an indication for surgical treatment was given. Between
2002 and 2006 a total number of 148 patients were included in
this clinical trial from seven German spine centers.
14.3.1 Patient Selection
Eligibility to participate in the study was limited to patients
having exclusively one level requiring surgical intervention. Criteria for surgical therapy were progressive sciatic pain with
futile conservative treatment or neurological deficits caused by
root nerve compression. Magnetic resonance imaging (MRI) of
the lumbar spine was mandatory. The trial was limited to
patients between 18 and 60 years of age, with a body mass
index (BMI) below 28.
Exclusion criteria to participating in the study included sclerotic changes, edema, Modic changes of type 2 or 3 in preoperative MRI, and spondylolisthesis. Patients with generalized
diseases or progressive neurological deficits were excluded, as
well as pregnancy.
3233
14.3.3 Transplantation
Cell implantation was performed 3 months after the primary
operative procedure to assure that the anulus had healed and
would contain the cells. Prior to intervention with the cells, an
MRI was used to detect possible early recurrent sequestration
or progressive degeneration. In the prepared solution for the
transplantation were more than 5 million living disc cells.
Under fluoroscopic control the affected disc was punctured
with a minimal caliber cannula opposite the side of the previous disc herniation procedure (▶ Fig. 14.3). Using a pressurevolume test
geons were able to place the cells with confidence that they
would be retained at the site of delivery.
Following cell transplantation, patients were placed for 24
hours in a lying position. After that time they were mobilized.
They were urged to wear a lumbar orthesis for the next 3 weeks
to provide an additional external stabilization to the treated
segments.
34
prior to the delivery of any chondrocytes, sur-
14.3.4 Follow-up
The primary clinical evaluation criterion used to evaluate patient recovery was the Oswestry Low Back Pain Disability Questionnaire (OPDQ). Secondary criteria included the 36-item
Short Form Health Survey (SF-36), Prolo Score,
Pain Disability Scale (QBPD), MRI, and X-ray evaluation.
All patients were scheduled for preoperative evaluation as
well as seen 3 months following sequestrectomy as the time
point for the transplantation in the treatment group. Additional
examinations were conducted 3, 6, 12, and 24 months after
transplantation. A long-term follow-up to evaluate durability of
treatment is planned for 10 years after transplantation.
35
Quebec Back
14.3.5 Results
An interim analysis with 28 patients was published in 2007 and
showed a clear benefit for the patients transplanted with autologous disc–derived cells.
Randomized Trial was not possible due to a lot of inconstancy
in the data collection between the centers.
In 2014 an evaluation of the data from 78 patients with a
mean age of 33.5 years (19–57 years) who were included
between 2002 and 2006 in the Euro Disc Trial through the
32
A final analysis of the Euro Disc
123
Nucleus Replacement and Repair: Autologous Disc Chondrocyte Transplantation
Fig. 14.3 Intraoperative picture of the fluoroscopically guided minimally invasive puncture of the intervertebral disc. (a) Fluoroscopic view after
puncture of the disc. (b) Pressure-volume test. (c) Transplantation.
Department of Neurosurgery at the BG Klinikum Bergmannstrost in Halle, Germany, was begun. Of the 36 patients
randomized into the treatment group, 3 patients dropped out
for personal reasons. From the remaining 33 patients, 21 were
successfully transplanted at the L5–S1 level and 12 at the L4–5
level following pressure-volume–test assurance in all patients
with annulus fibrous (AF) containment before transplantation.
The control group comprised 35 patients with disc herniation
at the L5–S1 level and 7 patients at the L4–5 level.
For descriptive analysis of efficacy, the total sum score as well
as the disability index of the OPDQ and the total sum score of
the QBPD were taken into account from the initial presurgical
presentation through the 2-year follow-up. 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 seen.
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 over the 2-year follow-up. The patients
in the control group did not sustain continual improvement. At
the 2-year follow-up we noticed in the control group an
increase in all measured clinical parameters. The difference was
not statistically significant but showed a clear benefit for the
treatment group (▶ Fig. 14.4).
A statistically significant difference was shown between the
groups by measure of the rate of reherniation of disc material.
The rate of recurrent herniation was 6.1% (2/33) in the autologous disc chondrocyte transplantation (ADCT) group. In the
control group we detected 16.7% (7/42) recurrent herniations.
From each group one patient had to be operated on again due
to development of neurological deficits from the recurrent
herniation.
14.4 Discussion
Cell transplantation in DDD is possible and the results of the
clinical study offer some optimism for the future treatment of
patients with intervertebral DDD. Autologous disc cell transplantation after sequestrectomy proved to be a safe and
technically feasible procedure in the hands of skilled and select
surgeons. Transplanted chondrocytes were shown to be viable
in situ and to create a functional matrix in preclinical work, and
124
Nucleus Replacement and Repair: Autologous Disc Chondrocyte Transplantation
Fig. 14.4 Description analysis of efficacy after 24
months. (a) Oswestry Disability Index. (b) Quebec Back Pain Disability Scale score. (c) Visual
Analog Scale (back pain). Abbreviations: ADCT,
autologous disc chondrocyte transplantation.
the assumption of translation of cell viability as one of the
accenting potentials of the clinical outcome seems likely.
The results for patients in the Euro Disc Randomized Trial
from the Department of Neurosurgery at the BG Klinikum Bergmannstrost provide strong evidence for both the safety and
efficiency of the disc-derived cell transplantation applied following sequestrectomy to delay or inhibit ongoing processes of
disc degeneration. After transplantation a clear decrease in
scores for the OPDQ, QBPD, and Visual Analog Scale (VAS) in
ADCT-treated patients for disability and pain were measured.
125
Nucleus Replacement and Repair: Autologous Disc Chondrocyte Transplantation
Assigning an ideal group of patients who might profit most
from the autologous disc cell transplantation needs additional
work in larger populations of patients as well in a broader
scope of clinical practice.
The technique of autologous disc cell transplantation is only
possible for patients who underwent a sequestrectomy. There
may be merit in transplanting disc cells at earlier stages of
degeneration prior to significant loss of matrix from the IVD,
but for autologous considerations this unfortunately requires
an operation. Surgery to harvest cell material in the early stages
of disc degeneration introduces the risk of infection to the disc
and the bone, plus the risk of nerve root injury and other potential complications, and therefore the larger medical community
has not been able to establish an ethical or medical foundation
for this consideration.
For patients with MRI findings graded according to the
36
Pfirrmann classification
between Grade I and Grade III
with accompanying symptomatic nerve root compression in
concert with a sequestered NP prolapse planning to undergo
a minimally invasive operative procedure, the possibility of
autologous disc cell transplantation might be an intervention that could be entertained. For other patients with intervertebral DDD who do not need to un dergo operative
treatment with sequestrectomy, a therapeutic option could
be the transplantation of adipose-derived stem cells, and
regenerative cells that are specifically expanded but allogenically derived. Our previous work in the animal model
demonstrated that these cells can be transplanted at surgery
using fluoroscopic guidance, and that these cells c an be
injected directly into the IVD with the expectation that they
will remain viable and produce appropriate, tissue-specific
33,37
matrix.
If future results of adipose-derived and regenerative cell
studies present promising outcomes, cell therapy might be
accepted as a safe and easy technique for producing cells for
minimally invasive transplant ation into a symptomatic
degenerative IVD without open operative intervention.
Among the first clinical studies using stem cells for treatment of intervertebral DDD, that by Orozco et al illustrates
the technical feasibility and safety of therapeutic interven-
38
tion with stem cells.
Ten patients with chronic back pain
diagnosed with lumbar disc degeneration with intact AF
were treated with autologous expanded bone marrow MSCs
injected into the NP area. The follow-u p time was one yea r
and there was no control group. Treated patient s exhibited
rapid improvement of pain and disability. The authors compare this favorably with the results of other procedures such
as spinal fusion or total disc replacement. Critics of this
study suggest that the lack of correlation of disc degeneration, a failure to adequately measure disc height and water
content, and a variety of etiologies confound the outcome
assessment. Those criticisms aside for what might constitute
an ideal study, the positive effects should be studied further
and could transfer to a controlled randomized study to
include more specificity in the inclusion criteria. To that
challenge, sources of cells also harbor choice. A particular
option for patients could be the transplantation of juvenile
allogeneic chondrocyte cells. Coric et al demonstrated i n a
small group of patients the technical feasibility and safety of
this procedure by using j uvenile allogenic chondrocyte cells
harvested from the articular surface of cadaveric donor tis-
39
These cells were transplanted using a fibrin glue–like
sue.
carrier, which has been shown in a separate pilot study to
be sufficient on its own account.
40
14.5 Conclusion
Total regeneration of the degenerated IVD is not currently considered a therapeutic assurance. The goals of regenerative medicine at this time are to prevent further progression of disc
degeneration and its associated symptoms. What has been
shown to date, and therefore been available in limited geographies and jurisdictions, is that expanded and transplanted
autologous cells are safe and appear to arrest if not reverse DDD
following treatment for sequestrectomy.
Our own experience embraces more than 140 patients
treated with autologous disc cell transplantation over the last
10 years. This is the largest number of patients with degenerated IVD disease treated with cell transplantation under
defined study conditions. All patients have benefited from
transplantation with reduced back pain as one measure of
an enhanced quality of life. All of the patients treated were
able to return to work after transplantation. There was no
postoperative back pain after cell transplantation, nor was there
any inflammatory complication such as spondylodiscitis or
local reaction after the cell transplantation in these patients.
Moreover, a stable disc height was reconciled in the MR images,
and a reduction in reherniation rate was more than 50% better
than that in the control group.
The principal limitation, however, comes from the fact that
the use of autologous chondrocytes requires the ex vivo expansion of cells, adding burdens of cost, time, and regulation that
add to the intricacy of the procedure beyond the medical interface. One way to circumvent these disadvantages is the use of a
one-step procedure, using stem cells obtained from autologous
adipose tissue. Ongoing studies will yield more information
about the possibility of using stem cells for regenerative therapies in intervertebral DDD.
Cell transplantation appears to present an effective treatment
option in DDD. A graft-versus-host reaction as a common problem after cell transplantation is reduced by the avascular nature
41
of the NP.
The effect of the transplantation is limited by the
survival of the transplanted cells in the hostile environment of
42
the degenerated disc.
The development of specialized carriers
that preserve the acidic environment of the IVD such as injectable hydrogels and atelocollagen as well as hyaluronic acid (HA)
are other factors that could facilitate the survival of transplanted cells and induce matrix production.
dence in the outcomes of the cell interventions for disc
treatment has been accepted in the medical lexicon, then it will
be possible for refinement and reimbursement within the
regenerative framework to achieve an equilibrium of medical
intention balanced in both economic and health ergonomics.
37
43,44
Once confi-
126