|
| |
 |
|
| REVIEW ARTICLE |
|
| Year : 2018 | Volume
: 11
| Issue : 4 | Page : 175-183 |
|
Advancements in the treatment of degenerative disc disease
Hassan Serhan
Department of Bioengineering, University of Toledo, Toledo, Ohio, USA
| Date of Web Publication | 9-Nov-2018 |
Correspondence Address:
Prof. Hassan Serhan
Department of Bioengineering, University of Toledo, Toledo, Ohio
USA
 Source of Support: None, Conflict of Interest: None  | 3 |
DOI: 10.4103/HMJ.HMJ_85_18
Low back pain is number one reason for disability in patients under the age of 45 year and the number two reason to see a doctor after flue in the USA. Early intervention for the treatment of patients with Degenerative Disc Disease (DDD) using regenerative medicine or ultra-minimal invasive approaches have gained traction over the past 20 years as alternatives to invasive, costly, and complicated surgical interventions. This review article discusses the pathophysiology of DDD and summarizes the literature encompassing the use of biologic-based therapies for DDD. Articles and patents published in the past 40 years were reviewed, cell-based, bimolecular or gene therapies, as well as companies investigating the utility of allogeneic and tissue-engineered intervertebral discs were included. Additionally, published and unpublished ongoing clinical trials were also included. These exciting non-invasive therapies have encouraging initial positive results across multiple strategies paving the road for a potentially thriving regenerative techniques and increase in the number of DDD clinical trials.
Keywords: Disc disease, pathophysiology, spinal fusion Disc disease, pathophysiology, spinal fusion
How to cite this article:
Serhan H. Advancements in the treatment of degenerative disc disease. Hamdan Med J 2018;11:175-83 |
| Introduction | |  |
While traditional therapies of spinal fusion and stabilisation have improved countless lives, these mechanical solutions incompletely address the underlying pathophysiology. They are more suitable to an end-stage degenerative disc disease (DDD), with little application for either prevention or early intervention. DDD particularly impacts the cervical and lumbar spine, accounting for the greatest burden of disability, where solutions offer an enormous opportunity for impacting health across large populations globally.[1],[2],[3] In general, the dissatisfaction with clinical outcomes of spine surgery, coupled with opportunity to help vast number of patients, creates an environment where innovations to bring forward solutions that are less invasive, are relevant across the continuum of care and potentially alter the natural history of DDD. Over the past three decades, we have filed several patents claiming the use of growth factors[4],[5],[6],[7] and cell therapies[8],[9] to halt and/or reverse disc degeneration. In addition, we have introduced even the concept of cross linking of the degenerated disc tissue[10],[11] to stabilize motion segments and eliminate pain. Most of these concepts are being investigated today for the treatment of DDD. Most of these concepts are being investigated today for the treatment of DDD.
While the development of DDD early intervention technologies has just started, and the adoption is very slow, however, with the increase of clinical data, it will become a viable, non-invasive option. This review article provides the technical views of the pathophysiology of DDD and the recent advancements in the treatment and reversing DDD.
| Pathophysiology of Degenerative Disc Disease | | |
The natural intervertebral disc (IVD) contains a jelly-like nucleus pulposus surrounded by the annulus fibrosus.[1] Under an axial load, the nucleus pulposus compresses and radially transfers that load to the annulus fibrosus. The laminated nature of the annulus fibrosus provides it with a high tensile strength and so allows it to expand radially in response to this transferred load.[12]
In a healthy IVD, the cells within the nucleus pulposus form only about 1% of the disc tissue by volume.[13] These cells produce an extracellular matrix (ECM) containing a high percentage of proteoglycans (PGs). These PGs contain sulphated functional groups that retain water, thereby providing the nucleus pulposus with its cushioning qualities. The nucleus pulposus cells may also secrete small amounts of cytokines as well as matrix metalloproteinases (MMPs).[14] These cytokines and MMPs help regulate the metabolism of the nucleus pulposus cells.[15]
The integrity of the IVD relies on a healthy balance between synthesis and degradation of the components of the ECM by the disc cells (especially PGs and collagens type II).[1] While the degrading IVD processes progress, higher concentrations of aberrant molecules appear (destructive proteolytic enzymes such as MMPs, abnormal PGs and collagens and more collagens type I and cytokines) which cause alterations in the structure and function of the matrix [Figure 1].[16]
The mechanical properties of ECM further become impaired because the nucleus starts losing more water and becomes more fibrous. This degradation leads to a less flexible nucleus pulposus and so changes the loading pattern within the disc, thereby possibly causing delamination of the annulus fibrosus.[10] These changes cause the cells to emit even more cytokines and up-regulate MMPs.[17],[18],[19],[20] In the late stages of degeneration, the disc begins to bulge (‘a herniated disc’) and then ultimately ruptures, causing the nucleus pulposus to contact the spinal cord and produce pain.[1],[13] Moreover, and once the endplates start to sclerose, it reduced capacity to provide nutrients to the cells and eliminate waste which in turn decreases cell viability and metabolism, resulting in further degradation of the ECM and accumulation of high levels of toxins that may cause nerve irritation and pain.[13] Destructive damage occurs in the nucleus, the endplates and the annulus. The endplates may rupture and in-to-out fissures appear in the annulus.[14]
| Current Treatment of Degenerative Disc Disease | | |
For most people, DDD can be successfully treated with conservative (meaning non-surgical) care consisting of medication to control inflammation and pain (steroid medications delivered either orally or through an epidural injection) and physical therapy and exercise. Surgery is only considered when patients have not achieved relief over 6 months of non-surgical care and/or are significantly constrained in performing everyday activities.
One of the primary difficulties in treating DDD is the lack of specific diagnostic tools and the fact that indications for surgery are poorly defined. Diagnostic specificity beyond the symptom of low back pain (LBP) or the presence of lumbar degeneration needs to be delineated such that outcome data can be effectively translated into clinical decision-making or evidence-based guidelines.[21]
Phillips et al. have evaluated surgical treatment for discogenic back pain in a systematic review of studies comparing fusion versus conservative care as well as studies comparing different fusion techniques for discogenic back pain.[22] After establishing strict inclusion and exclusion criteria for the publications, they reviewed 26 studies. Six papers reported on prospective randomised studies comparing fusion versus non-surgical therapy in patients with moderate-to-severe discogenic LBP. Results showed 35.3% improvement in the surgical group (547 patients) and 20% improvement in the non-surgical group (372 patients). Twelve prospective randomized studies were reviewed comparing various fusion techniques. The weighted average results in the 12 studies were 43.3% improvement in back pain (1420 patients) with a reoperation rate of 12.5% over at least 12 months of follow-up.[20] [Figure 2], shows a Typical Two Levels Instrumented lumbar interbody fusion with 12 months follow-up. | Figure 2: Typical Instrumented lumbar interbody fusion L3–4 and L4–5: (a) preoperative lateral X-ray, (b) immediately post-operative images, (c) 12 months’ post-operative X-rays illustrating solid fusion across instrumented segments
Click here to view |
Artificial disc replacement has also seen an increase as an alternative intervention for patients with DDD over the past several years. The purported benefits of lumbar artificial disc replacement over fusion surgeries include maintaining lumbar spine range of motion, which may reduce adjacent segment degeneration compared to fusion. In a meta-analysis recently published, the Jacobs et al. found that in one study comparing disc replacement to rehabilitation, there was an advantage for surgery, but it did not meet the predefined threshold for a clinically important difference. Another six studies compared disc replacement with fusion and found slight, non-significant improvements of 5.2 mm in visual analogue scale (VAS) back pain and 4.3 points improvement in Oswestry Disability Index scores.[23] Four studies have been published detailing the results of comparing fusion to artificial discs for the treatment of discogenic LBP. These are all prospective randomised Food and Drug Administration (FDA) investigational device exemption studies.[24],[25],[26] These studies, along with others, demonstrate the difficulty in surgically treating discogenic LBP [Figure 3]. | Figure 3: Charite lumbar total disc replacement L5–S1 (DePuy Synthes Spine)
Click here to view |
A study conducted at Thomas Jefferson University Hospital found that patients with back pain and concordant discography did not demonstrate a significant difference in outcome measures of pain, health status, satisfaction or disability based on whether the patient elected for fusion or non-operative treatment.[27]
Dissatisfaction in the clinical outcomes of fusion and total disc replacement for DDD has created an opportunity to investigate less invasive early intervention as a viable treatment option for reducing pain and improving function in patients with chronic LBP such as intradiscal cell or growth factor injection therapies.
| Non-Surgical Early Intervention for Degenerative Disc Disease | | |
[Figure 4] illustrates the degenerative cascade of a lumbar disc and lists the current and future potential non-surgical early intervention. Effective early intervention does not only reduce the pain but also has the potential to reverse the degenerative cascade and stop the progression of DDD and to restore disc height and function. There are two distinct approaches that are currently pursued for non-surgical early intervention: (1) intradiscal cell therapies and (2) injectable growth factor/molecules. | Figure 4: The disc degenerative cascade using the Thompson Classifications and current treatments and potential non-surgical early intervention
Click here to view |
Intradiscal cell therapy
During IVD degeneration, matrix composition and microenvironment changes have been observed. These changes include increased cell senescence and death, less production of PGs and collagen II, increased proteinases and cytokines and acidic pH.[28] The decrease in NP cells seems to be the trigger of disc degeneration, and therefore, replenishing cells could be a possible solution to decelerate further disc degeneration.[29]
Today, allogeneic and autologous cells are being investigated to repopulate the cells in the degenerative disc and to restore functional tissue through matrix synthesis by implanted cells and potential beneficial influences on native cells [Figure 5]. | Figure 5: Allogeneic and autologous stem cells, chondrocytic cells, fibroblast cells and expanded allogeneic disc cells proposed for the treatment of lumbar degenerative disc disease
Click here to view |
Autologous cell-based therapies
There is mounting evidence to support the use of biologic and cell-based therapies for chronic discogenic LBP.[30],[31],[32] Mesenchymal stem cells (MSCs) are considered analogous to perivascular cells or pericytes and are found virtually anywhere in the body with significant vasculature.[33] MSCs have the ability to differentiate into cells of diverse mesodermal lineages and have the capacity for self-renewal.[34] Many of regenerative healing properties of MSCs are the result of regulatory characteristics, including immunomodulation and paracrine signal secretion that prevents apoptosis, coordinates cellular repair and provides crucial components to block excessive inflammation.[33] There have been numerous studies utilising MSCs to enhance tissue repair and to decrease inflammatory damage in both in vitro laboratory studies and in vivo preclinical models.[1],[11],[12],[13],[14],[15],[16],[17],[18],[19],[35],[36],[37],[38] One study has shown that both the MSC population and these other nucleated cell types have healing properties and may contribute in a synergistic fashion to the healing seen in preclinical studies.[34] This indicates that while the composition of the injection may vary from person to person and contain different cell types in unknown ratios, the different contributions of the multiple cell lines help account for some of the demonstrated and potential healing benefits.
An increasing number of studies have demonstrated the ability of both bone marrow MSCs and adipose-derived MSCs to differentiate into discogenic cells.[39],[40],[41] The most common location of MSC extraction is bone marrow, commonly used in the form of bone marrow concentrated cells (BMCs). Pettine et al. published 1- and 2-year follow-up from a study assessing the safety and efficacy of BMCs as an alternative to surgery for discogenic back pain at one or two levels.[42],[43] The study showed magnetic resonance imaging (MRI) evidence of disc rehydration in 8/20 patients and significant decreases in VAS pain scores and Oswestry Disability Index scores from baseline to 2 years.
Allogeneic cell-based technologies
Mesoblast,[44] DiscGenics[45] and SpinalCyte[46] are the leading companies that are conducting clinical trials with allogeneic cell-based therapies in an attempt to halt degeneration and/or reverse the degenerative cascade of lumbar disc.
Mesoblast
Mesoblast uses 6 million expanded allogeneic mesenchymal precursor cells (MPCs) that are injected directly into a targeted disc in an outpatient procedure. Preclinical studies have established that MPCs have anti-inflammatory effects and secrete multiple paracrine factors that stimulate new proteoglycan and collagen synthesis by chondrocytes in vitro and by resident cells in the nucleus and annulus in vivo. MPCs have also been shown to produce anti-inflammation factors.[47],[48],[49]
In March 2017, Mesoblast released their phase II 36-month follow-up results which showed that a single intradiscal injection of 6 million MPCs resulted in meaningful improvements in both pain and function. Currently, Mesoblast is in the process of enrolling 360 patients in their phase III randomised, double-blind, placebo-controlled study.
DiscGenics
DiscGenics isolate cells directly from donor adult human disc tissue and expand these cells into therapeutic progenitor cells (discogenic cells). Since 2012, extensive preclinical evaluation has been performed on discogenic cells and injectable discogenic cell therapy (IDCT) utilising a wide variety of scientific approaches including in vitro assays, microscopy, biochemical evaluations and in vivo modelling. The findings have been presented at both national and international scientific conferences.[50],[51],[52]
In October 2017, DiscGenic received the U.S. FDA acceptance for initiating clinical Investigational New Drug (IND) of its IDCT. DiscGenics’ IND is a phase I/II prospective, randomised, double-blinded, vehicle- and placebo-controlled, to evaluate the safety and preliminary efficacy of IDCT in subjects with single-level, symptomatic lumbar IVD degeneration. The 60-subject trial is expected to begin enrolling in the U.S. in Q3 2018 [Figure 6]. | Figure 6: Flowchart illustrating the process of isolating and expanding discogenic cells
Click here to view |
SpinalCyte
Fibroblasts are the least specialised cells in the connective tissue family that secrete a non-rigid extracellular matrix, including type I and/or type II collagen. Human dermal fibroblasts (HDFs) have the potential to differentiate into a chondrocyte-like cell, which are similar cell types that make up the IVD.[53] HDFs can be removed easily via a punch biopsy and expanded before being directly injected into the injured spinal disc region.[54]
Preclinical and clinical studies have shown that normal HDFs (nHDFs) embedded in human collagen-based extracellular matrix can integrate well into the host and help heal surgical wounds.[55],[56]
Preclinical studies conducted by SpinalCyte illustrate that HDF cells are a promising option for cell therapy that may restore structure and height and reduce symptoms of degenerated discs.[46] In other preclinical studies, discs showed an increased expression of structural genes, such as collagen type I and II, and the contents of structural proteins, such as proteoglycan.[57]
In March 2017, SpinalCyte announced the first injection of fibroblasts for regeneration of the spinal disc. SpinalCyte is preparing for IND phase I submission and expects to enter clinical trials in the near future. SpinalCyte aims to show that using its off-the-shelf, allogeneic ‘pre-packaged’ cell therapy product, CybroCell will lead to a reduction in pain, improved function and regeneration of damaged discs.
NuQu by ISTO
ISTO's NuQu uses expanded allogeneic juvenile cartilage chondrocytic cells. Several preclinical studies have shown the regenerative effects of allogeneic non-disc-derived chondrocytes on disc repair in animal models.[32],[58],[59] After the positive preclinical studies, ISTO initiated a phase I single-arm, prospective feasibility study for the treatment of DDD for single-level DDD using NuQu, the results of phase I study were promising[60] and a subsequent prospective, randomised, double-blinded, placebo-controlled study was initiated. ISTO completed enrolment of its phase II clinical trial; however, ISTO has terminated the programme and stopped the study after completion of phase II, most probably due to statistical equivalency between the treatment arm and placebo.[61]
| Growth Factors | | |
Biological therapeutic approaches such as injecting recombinant growth factor or exogenous protein are being investigated to reverse DDD. Growth factors can boost native chondrocytic cell production by up-regulating production of anabolic ECM proteins and down-regulating catabolic factors.[62]
Almost 10 years ago, a couple of FDA IND Phase II and Phase II studies were initiated to evaluate the safety and effect of both OP-1 (MP-7) and recombinant human growth/differentiation factor-5 (rhGDF-5) (bone morphogenic protein 14 [BMP-14]). Both programmes were terminated prematurely as they failed to show anticipated significant benefits. Some of the challenge with growth factors could be their short biologic half-lives (hours/days) especially limited in chronic conditions, such as DDD. Furthermore, in a relatively advanced degenerative condition, the supply of nutrients is disturbed and stimulation of cellular activity by growth factors may result in an increased demand for nutrients, eventually inducing an adverse event. Growth factors clearly improve disc structure in in vivo animal studies, will this correlate with pain improvement in humans, only double-blinded randomised clinical trials will tell[Figure 7]! | Figure 7: Proposed growth factors: exogenous protein for the treatment of lumbar degenerative disc disease
Click here to view |
AnGen GM Inc
Nuclear factor-kappa B (NF-κB) is a gene transcriptional regulator of inflammatory cytokines. NF-κB decoy oligonucleotide inhibits production of those disease factors in the study using IVD cells.[63] The efficacy was also indicated in the disc degeneration animal model tests.[64] NF-κB decoy oligonucleotide is being considered as new therapeutic drug which has analgesic effect toward chronic lower back pain as well as possibility to be effective as a treatment for disc degeneration.[65]
Yuhan
Yuhan's YH14618 is a 7-amino acid peptide derived from a conserved region of biglycan that binds to transforming growth factor-beta 1 (TGFb1) and induces preferential down-regulation of Smad1/5/8 phosphorylation, suppressing further degeneration and inhibiting TGFb1-induced NGF expression. Phase I randomised study of intradiscal injection of YH14618 was reported at NASS 2015.[66] With the excellent safety and promising therapeutic efficacy, a Phase IIb study was initiated to determine the therapeutically effective dose in patients with symptomatic lumbar DDD. In October 2016, Kwon et al. reported that their potential breakthrough drug YH14618 flunked phase II clinical trials as it failed to show anticipated benefits.[67]
Stayble
STA-363 is based on an endogenous small molecule together with a contrast agent to assure accurate injection. The company indicates that an injection of STA-363 will stabilise the segment by transforming the nucleus pulposus into connective tissue and by rigidifying the annulus fibrosus. By transforming the disc into connective tissue, STA-363 reduces both production of pain-generating molecules and their spread to spinal nerves.[68]
Treatment with STA-363 is presumed to last the patient's entire life and require minimal rehabilitation.
In March 2017, Stayble Therapeutics initiated 15 patients phase I randomised, double-blinded, placebo-controlled, single ascending dose to investigate the safety, local tolerability and transformation of nucleus pulposus following intradiscal injection of STA-363 or placebo in patients with discogenic LBP.
Intralink-Spine
Non-surgical exogenous crosslinking therapy (Rejuve) is based on the injection of protein cross-linking molecule into a degenerative disc to restore its mechanical properties[10] and also to potentially increase the permeability of the tissue and so facilitate the exchange of waste products and nutrients. Preclinical studies showed that Rejuve immediately and permanently increases fibre bonds in the tissue matrix to provide a mechanically stronger tear-resistant tissue.[69] In addition, crosslink augmentation had positive effects on the mechanical properties of the annulus fibrosus in that it increased the ultimate strength, yield strength, toughness and modulus in the principal stress directions.[10],[70],[71]
Intralink-Spine has conducted a pilot study in Malaysia in 2016 using Rejuve. All of the five patients enrolled in pilot study had excellent results at 3-month post-procedure and 80% had excellent results at 6-months post-procedure. All four of our original five patients that have reached the 12-month mark continue to do well. Intralink-Spine believes the Réjuve System is going to change the landscape for the treatment of LBP.
DePuy Synthes recombinant human growth/differentiation factor-5
GDF-5 or BMP-14 is known to influence the growth and differentiation of various tissues, including the IVD. in vitro and in vivo experiments have shown GDF-5 to stimulate gene expression and synthesis of ECM proteins such as type II collagen and aggrecan.[72],[73] After the successful completion of Phase I with promising results, a phase II multicentre, randomised, double-blind, placebo-controlled clinical trial was initiated in September 2014. Phase II was designed to evaluate the safety and tolerability of intradiscal rhGDF-5 in subjects with early lumbar disc degeneration.[74] Phase II clinical trials failed to show anticipated significant benefits.
| Challenges With Degenerative Disc Disease | | |
The first issue is that sources of axial LBP are many, including but not limited to soft tissues, neurologic, articular and discogenic. Of all these pathologies, the disc is felt to be the most common link underlying axial and neurologic disease, and thus, DDD is of great interest as an innovation target.[17],[18] A pathophysiologic mechanism that may include one or a combination of mechanical and biochemical factors is an alternative explanation that is accompanied by less paradox than a purely structural and mechanical paradigm.[19],[20] The clinical features of many cases of LBP are inadequately explained by anatomic abnormalities alone, and the poor sensitivity and specificity of MRI and discography testifies to this problem.[75],[76]
The second issue is the significant effects in the placebo arm. Recent studies have demonstrated that some therapies for LBP are not superior to placebo controls in double-blind randomised clinical trials[77],[78] or are of only borderline increased efficacy.[79] Without a doubt, some of these improvements are due to normal declining of symptoms and regression to the mean.[80] Recent evidence suggests that beyond such spontaneous improvement, a significant percentage of these responses are due to placebo effects, i.e., the psychosocial effects of the therapeutic encounter, including its interactions, rituals and symbols.[81] Bar et al. performed post hoc comparison using data from four similar studies conducted at a single site that were prospective randomised controlled and double-blinded studies [Figure 8].[82] The results indicate that saline may offer patients pain resolution and decreases disability or may merely introduce less substance reaction and injection trauma. They noted a 50% or greater improvement observed for saline injected patients. | Figure 8: Placebo and possibly therapeutic effect of saline on degenerative disc disease
Click here to view |
| Future Clinical Indications for the Use of Cell or Growth Factor Injection Therapies | | |
A large number of patients have discogenic LBP which is often linked with twisting and bending injuries. Luckily, the majority of patients respond to rest, activity modification, anti-inflammatory medications and physical therapy. However, some patients develop chronic symptoms that require surgical intervention. Currently, the gold standard surgical treatment is decompression and stabilisation, fusion or total disc replacement, dynamic systems such as pedicle screw-based devices and interspinous spacers. Because selection of surgical treatments depends on the severity of degeneration, early non-surgical intervention is also affected by the different stages of disc degeneration. For early-to-moderately degenerated disc without significant biomechanical changes of the motion segment, growth factor and cell therapy injections have the potential to replenish the matrix, restore disc height and possibly relieve the patient's discogenic LBP.
In this decade, there has been a dramatic improvement in the understanding of potential growth factors and cell therapies application for patients with DDD. Despite this great interest in the use of growth factors and cell therapies, short biologic half-lives of growth factors and cells survival rate post injection, interaction with complicated microenvironment and detail functions and pain associated with DDD are not fully understood. With the high placebo effects and the limited understanding of DDD, double-blinded randomised controlled clinical studies are needed to assess efficacy and safety of these emerging therapies.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Urban JP, Roberts S. Degeneration of the intervertebral disc. Arthritis Res Ther 2003;5:120-30.  |
| 2. | Maniadakis N, Gray A. The economic burden of back pain in the UK. Pain 2000;84:95-103. |
| 3. | van Tulder MW, Koes BW, Bouter LM. A cost-of-illness study of back pain in the Netherlands. Pain 1995;62:233-40. |
| 4. | Attawia M, DiMauro TM, Serhan H, Kadiyal S, Urbahns D, Collins G, et al. US 8067397 B2, Transdiscal Administration of Cycline Compounds; August, 2003. |
| 5. | Serhan H, DiMauro TM, Attawia M, Grace M, Kadiyal S, Urbahns D, et al. US 7429378 B2, Transdiscal Administration of High Affinity anti-MMP Inhibitors; September, 2008. |
| 6. | DiMauro T, Serhan H, Attawia M. US 7344716 B2, US 20140199322 A1, Transdiscal Administration of Specific Inhibitors of Pro-Inflammatory Cytokines; May, 2003. |
| 7. | DiMauro TM, Serhan H, Attawia M. US 8877193 B2, Transdiscal Administration of anti-TNFα Antibodies and Growth Differentiation Factors; November, 2008. |
| 8. | Serhan H, Slivka M. US 20050071012 A1, Methods and Devices to Replace Spinal Disc Nucleus Pulposus; September, 2003. |
| 9. | Attawia M, Serhan H, DiMauro T, Grace M, Urbahns D. US 20040229786 A1, Autologous Treatment of Degenerated Disc with Cells; November, 2003. |
| 10. | Slivka M, Serhan H. US 20050209699 A1, Method for Nonsurgical Treatment of the Nucleus Pulposus of the Intervertebral Disc Using Genipin or Proanthrocyanidin, and Kit Therefor; March, 2005. |
| 11. | Serhan H, Slivka M. US 7294617 B2 Method for Nonsurgical Treatment of the Intervertebral Disc and Kit Therefor; March, 2002. |
| 12. | Inkinen RI, Lammi MJ, Lehmonen S, Puustjärvi K, Kääpä E, Tammi MI, et al. Relative increase of biglycan and decorin and altered chondroitin sulfate epitopes in the degenerating human intervertebral disc. J Rheumatol 1998;25:506-14. |
| 13. | Pattappa G, Li Z, Peroglio M, Wismer N, Alini M, Grad S, et al. Diversity of intervertebral disc cells: Phenotype and function. J Anat 2012;221:480-96. |
| 14. | Lyons G, Eisenstein SM, Sweet MB. Biochemical changes in intervertebral disc degeneration. Biochim Biophys Acta 1981;673:443-53. |
| 15. | Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM, et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol 2013;182:2310-21. |
| 16. | |
| 17. | Maroudas A, Stockwell RA, Nachemson A, Urban J. Factors involved in the nutrition of the human lumbar intervertebral disc: Cellularity and diffusion of glucose in vitro. J Anat 1975;120:113-30. |
| 18. | Gruber HE, Hanley EN Jr. Analysis of aging and degeneration of the human intervertebral disc. Comparison of surgical specimens with normal controls. Spine (Phila Pa 1976) 1998;23:751-7. |
| 19. | Weiler C, Nerlich AG, Zipperer J, Bachmeier BE, Boos N. 2002 SSE award competition in basic science: Expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption. Eur Spine J 2002;11:308-20. |
| 20. | Adams MA, McNally DS, Dolan P. ‘Stress’ distributions inside intervertebral discs. The effects of age and degeneration. J Bone Joint Surg Br 1996;78:965-72. |
| 21. | Glassman SD, Carreon LY, Djurasovic M, Dimar JR, Johnson JR, Puno RM, et al. Lumbar fusion outcomes stratified by specific diagnostic indication. Spine J 2009;9:13-21. |
| 22. | Phillips FM, Slosar PJ, Youssef JA, Andersson G, Papatheofanis F. Lumbar spine fusion for chronic low back pain due to degenerative disc disease: A systematic review. Spine (Phila Pa 1976) 2013;38:E409-22. |
| 23. | Jacobs WC, van der Gaag NA, Kruyt MC, Tuschel A, de Kleuver M, Peul WC, et al. Total disc replacement for chronic discogenic low back pain: A Cochrane review. Spine (Phila Pa 1976) 2013;38:24-36. |
| 24. | Guyer RD, McAfee PC, Banco RJ, Bitan FD, Cappuccino A, Geisler FH, et al. Prospective, randomized, multicenter food and drug administration investigational device exemption study of lumbar total disc replacement with the CHARITE artificial disc versus lumbar fusion: Five-year follow-up. Spine J 2009;9:374-86. |
| 25. | Siepe CJ, Heider F, Wiechert K, Hitzl W, Ishak B, Mayer MH, et al. Mid- to long-term results of total lumbar disc replacement: A prospective analysis with 5- to 10-year follow-up. Spine J 2014;14:1417-31. |
| 26. | Garcia R Jr., Yue JJ, Blumenthal S, Coric D, Patel VV, Leary SP, et al. Lumbar total disc replacement for discogenic low back pain: Two-year outcomes of the activL multicenter randomized controlled IDE clinical trial. Spine (Phila Pa 1976) 2015;40:1873-81. |
| 27. | Smith JS, Sidhu G, Bode K, Gendelberg D, Maltenfort M, Ibrahimi D, et al. Operative and nonoperative treatment approaches for lumbar degenerative disc disease have similar long-term clinical outcomes among patients with positive discography. World Neurosurg 2014;82:872-8. |
| 28. | Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976) 2006;31:2151-61. |
| 29. | Leung VY, Chan D, Cheung KM. Regeneration of intervertebral disc by mesenchymal stem cells: Potentials, limitations, and future direction. Eur Spine J 2006;15 Suppl 3:S406-13. |
| 30. | Sakai D, Andersson GB. Stem cell therapy for intervertebral disc regeneration: Obstacles and solutions. Nat Rev Rheumatol 2015;11:243-56. |
| 31. | Yim RL, Lee JT, Bow CH, Meij B, Leung V, Cheung KM, et al. Asystematic review of the safety and efficacy of mesenchymal stem cells for disc degeneration: Insights and future directions for regenerative therapeutics. Stem Cells Dev 2014;23:2553-67. |
| 32. | Acosta FL Jr., Metz L, Adkisson HD, Liu J, Carruthers-Liebenberg E, Milliman C, et al. Porcine intervertebral disc repair using allogeneic juvenile articular chondrocytes or mesenchymal stem cells. Tissue Eng Part A 2011;17:3045-55. |
| 33. | Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 2013;45:e54. |
| 34. | Otsuru S, Gordon PL, Shimono K, Jethva R, Marino R, Phillips CL, et al. Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms. Blood 2012;120:1933-41. |
| 35. | Chang CH, Kuo TF, Lin FH, Wang JH, Hsu YM, Huang HT, et al. Tissue engineering-based cartilage repair with mesenchymal stem cells in a porcine model. J Orthop Res 2011;29:1874-80. |
| 36. | Lee KB, Hui JH, Song IC, Ardany L, Lee EH. Injectable mesenchymal stem cell therapy for large cartilage defects – A porcine model. Stem Cells 2007;25:2964-71. |
| 37. | Sato M, Uchida K, Nakajima H, Miyazaki T, Guerrero AR, Watanabe S, et al. Direct transplantation of mesenchymal stem cells into the knee joints of hartley strain guinea pigs with spontaneous osteoarthritis. Arthritis Res Ther 2012;14:R31. |
| 38. | Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 2003;48:3464-74. |
| 39. | Centeno C, Markle J, Dodson E, Stemper I, Williams CJ, Hyzy M, et al. Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: A pilot study on safety and efficacy. J Transl Med 2017;15:197. |
| 40. | Teixeira GQ, Pereira CL, Ferreira JR, Maia AF, Gomez-Lazaro M, Barbosa MA, et al. Immunomodulation of human mesenchymal stem/Stromal cells in intervertebral disc degeneration: Insights from a proinflammatory/Degenerative ex vivo model. Spine (Phila Pa 1976) 2018;43:E673-82. |
| 41. | Steffen F, Smolders LA, Roentgen AM, Bertolo A, Stoyanov J. Bone marrow-derived mesenchymal stem cells as autologous therapy in dogs with naturally occurring intervertebral disc disease: Feasibility, safety, and preliminary results. Tissue Eng Part C Methods 2017;23:643-51. |
| 42. | Pettine K, Suzuki R, Sand T, Murphy M. Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up. Int Orthop 2016;40:135-40. |
| 43. | Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells 2015;33:146-56. |
| 44. | |
| 45. | |
| 46. | Chee A, Shi P, Cha T, Kao TH, Yang SH, Zhu J, et al. Cell therapy with human dermal fibroblasts enhances intervertebral disk repair and decreases inflammation in the rabbit model. Global Spine J 2016;6:771-9. |
| 47. | Andersson GB. Epidemiological features of chronic low-back pain. Lancet 1999;354:581-5. |
| 48. | Freburger JK, Holmes GM, Agans RP, Jackman AM, Darter JD, Wallace AS, et al. The rising prevalence of chronic low back pain. Arch Intern Med 2009;169:251-8. |
| 49. | DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does age play a role? Pain Med 2011;12:224-33. |
| 50. | Silverman LI, Chintalacharuvu S, Howard A, Foley KT. Large Animal Model Development for Use in Testing a Novel Cell Therapy for Degenerative Disc Disease. Podium Presentation. Lumbar Spine Research Society 8 th Annual Meeting. Chicago; 9-10 April, 2015. |
| 51. | Silverman LI, Dulatova G, Gupta K, Tandeski T, Chintalacharuvu C, Howard A, et al. Comparative Viability, Potency and in vivo Efficacy of a Fresh or Cryopreserved Cell Therapy for the Treatment of Degenerative Disc Disease. Poster Presentation American Society of Gene and Cell Therapy Annual Meeting. New Orleans LA; 13-15 May, 2015. |
| 52. | Silverman LI, Tandeski T, Gupta K, Foley KT. Non-Immunogenic and Anti-Inflammatory Properties of Discogenic Cells, a Novel Cell Population Used for the Treatment of Degenerative Disc Disease. Podium Presentation. The American Academy of Neurological Surgeons Annual Meeting. Florida; 17-20 September, 2014. |
| 53. | Junker JP, Sommar P, Skog M, Johnson H, Kratz G. Adipogenic, chondrogenic and osteogenic differentiation of clonally derived human dermal fibroblasts. Cells Tissues Organs 2010;191:105-18. |
| 54. | |
| 55. | Boyd M, Flasza M, Johnson PA, Roberts JS, Kemp P. Integration and persistence of an investigational human living skin equivalent (ICX-SKN) in human surgical wounds. Regen Med 2007;2:363-70. |
| 56. | Flasza M, Kemp P, Shering D, Qiao J, Marshall D, Bokta A, et al. Development and manufacture of an investigational human living dermal equivalent (ICX-SKN). Regen Med 2007;2:903-18. |
| 57. | Singh M, Pierpoint M, Mikos AG, Kasper FK. Chondrogenic differentiation of neonatal human dermal fibroblasts encapsulated in alginate beads with hydrostatic compression under hypoxic conditions in the presence of bone morphogenetic protein-2. J Biomed Mater Res A 2011;98:412-24. |
| 58. | Adkisson HD 4 th, Martin JA, Amendola RL, Milliman C, Mauch KA, Katwal AB, et al. The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage. Am J Sports Med 2010;38:1324-33. |
| 59. | Adkisson HD, Gillis MP, Davis EC, Maloney W, Hruska KA. In vitro generation of scaffold independent neocartilage. Clin Orthop Relat Res 2001;(391 Suppl):S280-94. |
| 60. | Coric D, Pettine K, Sumich A, Boltes MO. Prospective study of disc repair with allogeneic chondrocytes presented at the 2012 joint spine section meeting. J Neurosurg Spine 2013;18:85-95. |
| 61. | |
| 62. | Masuda K, Imai Y, Okuma M, Muehleman C, Nakagawa K, Akeda K, et al. Osteogenic protein-1 injection into a degenerated disc induces the restoration of disc height and structural changes in the rabbit anular puncture model. Spine (Phila Pa 1976) 2006;31:742-54. |
| 63. | Suzuki M, Inoue G, Gemba T, Watanabe T, Ito T, Koshi T, et al. Nuclear factor-kappa B decoy suppresses nerve injury and improves mechanical allodynia and thermal hyperalgesia in a rat lumbar disc herniation model. Eur Spine J 2009;18:1001-7. |
| 64. | Feng C, Zhang Y, Yang M, Lan M, Liu H, Huang B, et al. Oxygen-sensing nox4 generates genotoxic ROS to induce premature senescence of nucleus pulposus cells through MAPK and NF- κ B pathways. Oxid Med Cell Longev 2017;2017:7426458. |
| 65. | |
| 66. | Kwon YJ, Kim ES, Kim SM, Park H, Byun HB, Nam SY. Intradiscal Injection of YH14618, a first-in-class disease-modifying therapy, reduces pain and improves daily activity in patients with symptomatic lumbar degenerative disc disease. Spine J 2015;15 Suppl: S119. |
| 67. | |
| 68. | |
| 69. | Hedman TP, Saito H, Vo C, Chuang SY. Exogenous cross-linking increases the stability of spinal motion segments. Spine (Phila Pa 1976) 2006;31:E480-5. |
| 70. | Slusarewicz P, Zhu K, Hedman T. Kinetic characterization and comparison of various protein crosslinking reagents for matrix modification. J Mater Sci Mater Med 2010;21:1175-81. |
| 71. | Kirking B, Hedman T, Criscione J. Changes in the interfacial shear resistance of disc annulus fibrosus from genipin crosslinking. J Biomech 2014;47:293-6. |
| 72. | Chujo T, An HS, Akeda K, Miyamoto K, Muehleman C, Attawia M, et al. Effects of growth differentiation factor-5 on the intervertebral disc – in vitro bovine study and in vivo rabbit disc degeneration model study. Spine (Phila Pa 1976) 2006;31:2909-17. |
| 73. | Walsh AJ, Bradford DS, Lotz JC. in vivo growth factor treatment of degenerated intervertebral discs. Spine (Phila Pa 1976) 2004;29:156-63. |
| 74. | A Multicenter, Randomized, Double-Blind, Placebo Controlled, Clinical Trial to Evaluate the Safety, Tolerability and Preliminary Effectiveness of 2 doses of Intradiscal rhGDF-5 (single administration) for the Treatment of Early Stage Lumbar Disc Degeneration; August, 2016. Available from: https://clinicaltrials.gov/ct2/show/results/NCT01124006?view=results. |
| 75. | Luoma K, Riihimäki H, Luukkonen R, Raininko R, Viikari-Juntura E, Lamminen A, et al. Low back pain in relation to lumbar disc degeneration. Spine (Phila Pa 1976) 2000;25:487-92. |
| 76. | Boden SD, Davis DO, Dina TS, Patronas NJ, Wiesel SW. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am 1990;72:403-8. |
| 77. | Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: Systematic review and meta-analysis of randomised placebo controlled trials. BMJ 2015;350:h1225. |
| 78. | Williams CM, Maher CG, Latimer J, McLachlan AJ, Hancock MJ, Day RO, et al. Efficacy of paracetamol for acute low-back pain: A double-blind, randomised controlled trial. Lancet 2014;384:1586-96. |
| 79. | Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW, Nonsteroidal anti-inflammatory drugs for low back pain: An updated Cochrane review. Spine (Phila Pa 1976) 2008;33:1766-74. |
| 80. | Rutherford BR, Mori S, Sneed JR, Pimontel MA, Roose SP. Contribution of spontaneous improvement to placebo response in depression: A meta-analytic review. J Psychiatr Res 2012;46:697-702. |
| 81. | Kaptchuk TJ, Miller FG. Placebo effects in medicine. N Engl J Med 2015;373:8-9. |
| 82. | |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
|
Search Pubmed for