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Intervertebral Disc: Int.Cartilage Repair Society, 2012 Annual Mtg Extended Abstracts
2012 International Cartilage Repair Society
May 12-15, 2012
Extended Abstracts (LINK PDF 7.63 MB 8,008,766 bytes)
Session 8.3 Intervertebral Disc
09:45 - 10:45 Room: St. François
Moderators: Rita Kandel (CA), Susan Chubinskaya (US)
R.Kandel University of Toronto
S. Chubinskaya Rush University, Chicago
8.3.1 Intervertebral Disc Tissue Engineering: Is it ready for weight bearing?
R. Kandel, Toronto/Canada
8.3.2 Current clinical treatment strategies and future concepts
S. Daisuke, Kanagawa, Isehara/Japan
8.3.3 Materials for intervertebral disc tissue engineering
R. Mauck, M.B. Fisher, D.M. Elliott, Philadelphia/US
ICRS- Intervertebral Disc Tissue Engineering: Is it ready for weight bearing?
Intervertebral Disc Tissue Engineering: Is it ready for weight bearing?
Degeneration of the intervertebral disc, which is composed of the annulus fibrosus (AF), nucleus pulposus (NP), and cartilage endplates, causes loss of disc function and can be associated with low back pain (1,2). Approximately 1 in 50 individuals become disabled by intervertebral disc degeneration; the annual total costs, which in 2004 in the United States alone, was estimated at over $100 billion. There is a growing consensus that the surgical treatments used currently for disc degeneration are not effective and cannot be further optimized; thus there is great interest in developing a biological therapy to treat the chronic pain that arises from disc degeneration (1,3).
Biological repair or replacement results in tissue that can remodel and respond to load, an outcome not achievable by current surgical therapies. Many different approaches to disc repair are being investigated. However a recent study raised concern about intradiscal injections and their potential to contribute to disc degeneration so a particular interest has developed in the use of regenerative medicine to generate an intervertebral disc that structurally and functionally resembles the in vivo disc (4).
To date, we have advanced significantly towards accomplishing this goal. Studies have described the formation of the nucleus pulposus tissue. However we do not yet know whether we require the presence of both nucleus pulposus cells and notochordal cells in this tissue or whether generating tissue by just nucleus pulposus cells alone will be sufficient to form tissue of appropriate quality to withstand weight bearing over the long term. Investigation into the role of notochordal cells in nucleus tissue is a subject of intense investigation currently and much attention is directed towards trying to develop methods to obtain pure populations of these cells. In contrast engineering the annulus fibrosus has been more problematic given its complex structure.
The annulus fibrosus surrounds the nucleus pulposus and has a cross-ply laminate structure consisting of between 10-25 lamellae, each composed of collagen fibres oriented parallel to each other and about 65o from the vertical, so every second lamella has the same orientation. Various approaches have been utilized to generate annulus fibrosus tissue ranging from the use of allograft tissue to in vitro generated annulus fibrosus tissue. (5,6). Annulus fibrosus cells are very responsive to their microenvironment. Our recent studies have shown that how a scaffold is pre-treated, such as coating it with fibronectin versus collagen or the amount of tension the cells experience can affect annulus cell and collagen alignment and thus tissue formation. Clearly creating annulus fibrosus tissue will require more study. An additional issue to be considered is ensuring that all the necessary components of the disc are replaced.
It likely will not be sufficient to replace only the annulus fibrosus and nucleus pulposus as studies have shown that an intact cartilage endplate may be necessary for maintenance of the nucleus pulposus tissue. Co-culture of in vitro-formed nucleus pulposus tissue with in vitro-formed cartilage resulted in increased aggrecan and collagen gene expression compared with that in NP tissue grown alone. In addition there was reduced expression of degradative enzymes, MMP-3, MMP-13, and ADAMTS-5. Expression of genes for tumor necrosis factor α (TNFα) and TACE in nucleus pulposus cells was higher when grown in the absence of cartilage and corresponded with increased TNFα protein levels. This suggests that chondrocytes may secrete a factor(s) that inhibits TNFα production and positively enhances tissue maintenance.
Loss of the cartilage endplate could be a potential mechanism explaining how changes in this tissue may contribute to the development of NP degenerative changes and suggesting that part of the disc replacement strategy must include repairing the cartilage endplate. Identifying a cell source to generate the different disc tissues is also another issue. Use of autogenous cells may be a problematic as studies in nucleus pulposus tissue engineering demonstrate that although nucleus pulposus tissue can be formed by the nucleus cells obtained from older animals (cows), they formed less tissue compared to cells obtained from younger animals (younger than adolescents). Interestingly the older cells had lower constitutive gene expression of collagen type II and aggrecan whereas collagen type I and link protein levels were similar to those of the younger cells. Metalloprotease (MMP) 13 gene and protein expression increased with age. There was no change in the levels of gene expression of MMP 2 and TIMP 1, 2, or 3 with age. Thus cells obtained from nucleus pulposus tissue harvested from younger or mature animals showed both genotypic and phenotypic differences in vitro. Although these changes may be circumvented by gene therapy the use of other sources of cells, such as stem cells, are being explored. Until we have markers that are definitively specific to the cells of the different disc tissues it will not be possible to use stem cells.
Finally the method to implant the biological replacement will have to be developed. The surgical approach will have to be optimized and then it will be necessary to ensure that the implanted disc will integrate to bone in the presence of weight bearing. Clearly although a biological disc replacement is not yet available we appear to be making great progress, and in some ways moving faster than that of cartilage tissue engineering. Furthermore our attempts to create a disc have provided insights as to the biology of the disc and some of the requirements that may be critical to successful generation of an intervertebral disc.
In the interim to ensure rapid translation into clinical practice once a biological disc replacement has been developed we should also be turning our attention to determining who would be a candidate for such a treatment, what is the optimal rehabilitation regimen, and how to define a successful outcome for those receiving a disc replacement.
1) Raj PP. Pain Pract. 2008; 8(1):18- 24.
2) Cheung K et al. The Spine J. 2010;10, 958-60.
3) Kandel et al. Eur Spine J Suppl 2008; 4:480-91.
4) Carragee EJ, Don AS, Hurwitz EL, Cuellar JM, Carrino JA, Herzog R. Spine (Phila Pa 1976). 2009;34:2338-45.
5) Bowles RD et al. PNAS 2011;108:13106-11
6) Luk KD and Ruan RK. Eur Spine J. 2008 Suppl 4:504-10.
Current clinical treatment strategies and future concepts
The intervertebral disc (IVD) functions as an essential load absorber between all vertebrae by allowing bending, flexion, and torsion of the spine. IVD degeneration is a cell-mediated response to progressive structural failure and causes instability of the vertebral motion segments that are responsible for neural compressive manifestations and low back pain. Prolonged segmental instability eventually leads to deformity of the spine and many clinical problems.
Current clinical concept, their limitations, and progress of future treatment investigations will be presented.
Treatment usually begins with non-operative modalities, such as physical therapy or methods for core strengthening; symptomatic medical treatment with non-steroidal anti-inflammatory medications is a further common method to reduce pain. Surgical methods are considered if conservative therapy fails.
Although only a small percentage of patients with disc disorders finally will undergo surgery, spinal surgery has been one of the fastest growing disciplines in the musculoskeletal field in recent years. Nevertheless, current treatment options are still a matter of controversial discussion. The standard surgical intervention has been spinal arthrodesis with the aim to immobilize the spinal segment, preferably by bony fusion. The aim is to cease mechanical cues and inflammatory processes causing pain and disability. However, compared to conservative treatment only small benefits could be achieved, as assessed in several clinical studies. In addition, the occurrence of adjacent segment disease should not be underestimated. With the goal to better preserve the biomechanics of the spine, total disc replacement has been introduced and has become part of surgical routine in recent years. Since this technology has not been able to demonstrate any significant advantage to the standard spinal arthrodesis and in contrast has faced considerable complication rates, it has been critically debated.
Other newer technologies include nucleus pulposus replacement or dynamic stabilization methods. Long-term clinical outcomes that may disclose any potential benefit of these new methods are not yet available; however the long-term success rates of all these procedures are estimated to be generally similar. Although in the main satisfying results can be achieved, all these treatment methods attempt to reduce pain but cannot repair the degenerated disc. In particular, they hardly can restore normal spine biomechanics and prevent degeneration of adjacent tissues.
Therefore new treatments are under development with the aim to restore disc height and biomechanical function. The objective of such new regenerative strategies is to generate healthy disc tissue or functional replacements that decelerate or reverse painful degeneration processes. A number of biological approaches such as molecular, gene, and cell based therapies have been investigated and have shown promising results in both in vitro and in vivo studies. Recently, cell transplantation based on the supplementation of matrix producing cells in an attempt to correct the decrease of matrix components, primarily proteoglycan and collagen, a major factor in disc degeneration has been under clinical trial.
The concept goes back to 1996, when Mochida et al. demonstrated the importance of preserving NP elements for preventing the acceleration of disc degeneration following discectomy. This clinical study opened a new area of research into replacement of the cells lost by pathological manifestations or surgical intervention, potentially retarding the progression of disc degeneration. To test this hypothesis, an animal model study, performed by Nishimura and Mochida, demonstrated that reinsertion of autologous fresh or cryopreserved NP cells slowed degeneration in the rat IVD.
Numerous subsequent studies have reported the efficacy of cell transplantation therapy using various animal models and donor cell types. The author’s lab has studied the potential of MSCs as an alternative cell source. They transplanted autologous MSCs tagged with the gene for green fluorescent protein (GFP) in rabbit disc degeneration model created by nucleus aspiration, and followed the GFP-labelled cells for a period of 48 weeks, tracking the effects using MRI and radiography.
They also used immunohistochemistry for chondroitin sulphate, keratin sulphate, collagen types I, II, and IV, HIF-1alpha and beta, HIF-2alpha and beta, glucose transporters GLUT-1 and GLUT-3, and MMP-2, and applied RT-PCR to assess expression of the genes for aggrecan, versican, collagen types I and II, IL-1b, IL-6, TNF-alpha, MMP-9, and MMP-13. MRI and radiographic results confirmed the regenerative effects of the procedure. GFP-positive cells were detected in the nucleus throughout the time course at proportions rising from 21% ± 6% at 2 weeks to 55% ± 8% at 48 weeks, which demonstrated the survival and proliferation of MSCs.
Immunohistochemistry showed positive staining for all proteoglycan epitopes and type II collagen in some of the GFP-positive cells. MSCs produced HIF-1alpha, MMP-2, and GLUT-3 with phenotypic activity comparable to NP cells. The RTPCR demonstrated significant restoration of aggrecan, versican, and type II collagen gene expression, and significant suppression of TNFalpha and IL-1b expression in the transplantation group. Thus, MSCs transplanted into degenerating discs in vivo can survive, proliferate, and differentiate into cells expressing the phenotype of NP cells with suppression of inflammatory genes.
In order to achieve a maximal effect in stem cell therapy for IVD disease, knowledge on cells, extracellular matrix and the microenvironment of the native disc must be extensively studied. Fully committed adult cells are cells that actively function as main cell population eventually going into apoptosis. Other than committed adult cells are the tissue specific somatic progenitor/stem cells which are an undifferentiated cells found among differentiated cells in tissue or organ that can renew itself. Stem cells are distributed around the body in various other ‘niches’. Evidence of existence of the small stem cell population has not been well studied in the IVD. In order to identify the somatic stem cell population that reside in the IVD, “stem cell markers” were immunohistochemically analyzed in rat, beagle and human IVDs.
The immunohistochemical analysis in rat IVD specimens revealed that most of these classical stem cell markers may not be useful in identifying endogenous stem cells in the disc. Especially, positivity of the hall mark markers CD90, CD105 and CD 166 was 85, 92 and 98 percent (n=5). This was far different from the standard characteristics of stem cells which reside in small population with inactive cell viability at rest and after initiation, shows high self-renewal and proliferative ability with multi-potent differentiation. Regarding other markers, no significant expression (0-10 percent) was detected for CD56, CD120a CD124 MHC class I, etc. in the rat disc, which may remain these markers as potential candidates. To note, negative expression in some of these markers may be a result of non-cross reactivity of the antibody to the rat.
Result of human disc specimens showed that CD56, 90 105,166 was expressed in some young disc cells in sparse areas, such as NP cells forming clusters but in old aged disc where cells are isolated in single cells, merely none of these markers were positive in most discs. To overcome the lack of stem cell population indicated by the results, identification of progenitor cells by marker analysis was continued through FACS analysis. By plotting the positivity of these markers through serial culture periods, we are able to detect cell markers which correlate with cell proliferation. As mentioned, stem/progenitor cell populations show little or decreased cell number at primary culture and give rise to rapid proliferation several weeks after, meaning potential for high self-renewal.
We also found that by culturing beagle NP cells in gels, several different colonies can be induced. These included sphere shaped colony and few adherent colonies. Number of adherent colonies increased with time with no change with culture period. On the other hand, change in number of sphere colonies formed showed correlation with proliferation curve pattern of progenitor cells. These findings provide useful information on the progenitor cell population in the IVD. Collectively, new techniques based on rigorous animal studies and clinical trials are on the way to be brought into future treatment of the intervertebral disc degeneration. Uncovering of cells and their microenvironment is needed to be investigated in parallel for obtaining maximal efficacy and safety.
1. Alini M, Sakai D, Eglin D, et al. Cells and Biomaterials for Intervertebral Disc Rgeneration. Synthesis Lectures on Tissue Engineering. Morgan and Claypool Publishers. 2010; 1-104.
2. Sakai D. Stem cell regeneration of the intervertebral disk. Orthop Clin North Am. 2011;42(4):555-62.
This work was supported in part by a Grant-in-Aid for Scientific Research and a Grant of The Science Frontier Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a grant from AO Spine International.
Materials for intervertebral disc tissue engineering
R. Mauck, M.B. Fisher, D.M. Elliott
Philadelphia/United States of America
Intervertebral disc (IVD) degeneration is linked to multiple causal factors, including age and genetics, mechanical fatigue, injury through trauma, continued exposure to vibrational loading, and mechanical overload. Disc degeneration progresses over time and impacts a large percentage of the world population. Low back pain in the U.S. is widespread in the general population, and limits activity in more than 50% of the population over the age of 55 . Lumbar disc degeneration has been strongly implicated as a causative factor in low back pain , and neither conservative treatments (stretching and exercise) nor surgical options (discectomy, fusion, and arthroplasty) restore disc structure or mechanical function. Indeed, fusion permanently locks adjacent vertebral bodies in place, while disc arthroplasty is relatively new to clinical practice and will likely suffer from the same problems as traditional implant materials – wear and the need for eventual replacement. As such, biomaterial and biologic interventions to regenerate a degenerate IVD would have a distinct competitive advantage over current clinical procedures, while also potentially reducing painful conditions and delaying or preventing the need for spinal fusion or replacement.
This talk will focus on the critical structure-function relationships of the native disc, with a particular focus on the annulus fibrosus, and highlight emerging biomaterials and cell-based methods designed to foster regeneration and/or produce functional analogues for the repair and/or replacement of this unique load-bearing structure.
The IVD is composed of the nucleus pulposus (NP), a hydrated, gelatinous structure, and the annulus fibrosus (AF), a multi-lamellar fibrocartilage that surrounds the NP between the vertebral bodies. The NP is structurally and mechanically isotropic and contains a network of type II collagen interspersed with proteoglycans, resulting in high water content within the tissue.
Conversely, the fibrocartilaginous AF has a high degree of structural organization over multiple length scales: aligned bundles of collagen fibers reside within each lamella and the direction of alignment alternates from one lamella to the next by 30° above and below the transverse plane [3, 4]. The resulting angle-ply laminate possesses pronounced mechanical anisotropy and nonlinearity, allowing the AF to support tension, shear, compression, and torsion . The NP and AF regions work in concert; when the disc is compressed, hydrostatic pressure in the NP increases, resulting in stresses along the circumferential direction of the AF, which are in turn resisted by the organized lamellar AF structure. Injury or degeneration to either portion of this composite can compromise overall disc mechanical function, and as such, methods have been devised to address failure in either or both components.
While disc degeneration can originate in multiple locations, tears within the AF region are especially pernicious as they can propagate to the NP region, eventually resulting in complete tears involving leakage of the NP (disc herniation). Along with herniation, there is often a loss of annulus tissue [6, 7]. In fact, annular tears are seen in more than half of the patients in early adulthood and are found in the majority of the elderly . Yet, the most common surgical treatment for disc herniation, e.g. microdiscectomy, does nothing to repair the AF, which has a limited intrinsic healing potential . As such, reherniation rates following these procedures can range from 5-15% [10-13], compromising long term disc health.
Given the prevalence of low back pain associated with damage or degeneration of all or part of the IVD, a host of products and devices have been developed, with some reaching the commercial market. These include products that restore pressurization in the NP region or mechanically augment the torn AF (i.e., suture, meshes, and reinforcing barriers) [7, 14]. While such approaches have shown promise in cadaveric studies, those focused on the AF do not recapitulate the structure or function of the native tissue, and thus, abnormal loading and continued degeneration may occur. Furthermore, the majority of these devices are inert, preventing integration with the native disc. Given these limitations in current commercial devices and clinical methods, a number of tissue engineering and regenerative medicine approaches have been pursued (for review, see ). These approaches have focused on the AF, the NP, or a combination of the two.
In most cases, the disc is separated into an NP region containing chondrocyte-like cells and an AF region containing fibroblast-like cells. These cellular subpopulations have been seeded in a variety of tissue engineering scaffolds or hydrogels to evaluate their ability to reconstitute the histological structure and composition of native tissue [15-19].
Scaffolds have included alginate and agarose hydrogels, collagen gels, collagen / glycosaminoglycan gels, collagen/hyaluronic acid scaffolds and collagen sponges, to name but a few [20-25]. These and other studies have established that disc cells can be maintained in three dimensional culture, that they produce plentiful ECM with time, and that certain mechanical, biological, and structural cues may foster construct maturation (i.e., a hydrogel for the NP and a porous/fibrous scaffold for the AF). More recently, multi-potential mesenchymal stem cells (MSCs) have been employed in a number of these scaffolding systems, with evidence of disc-like matrix formation in these 3D biomaterial contexts . While these studies highlight the potential to generate disc-like neo-tissue by combining cells and scaffolds, for many years, little consideration was given to the mechanical properties and function of these engineered materials within a load bearing environment. The mechanical requirements for an engineered disc construct will depend largely on its intended location and use.
An AF ‘patch’ would be expected to integrate across an AF fissure, resist further NP herniation, and transfer tensile forces with disc compression. An NP construct would be expected to fill the central region of the disc and pressurize and engage the AF with loading. A total biologic disc replacement would be expected to carry out both of these critical functions, while also integrating seamlessly with the surrounding vertebral bodies. Depending on application, these materials or constructs might be required to match native tissue at the time of implantation (if early remobilization is expected) or could conceivably mature in place to match these properties (if a period of protection from loading were possible). In either format or application, these engineered materials would eventually be expected to withstand dynamic mechanical loading (at multiple body weights) in multiple directions, consistent with the complex and demanding loading environment of the disc with normal activities.
While these requirements may seem insurmountable, the last decade has borne witness to marked progress in the area of disc tissue engineering. For example, in seminal work in the field, Bonassar and colleagues created a composite disc by encapsulating NP cells in an alginate hydrogel surrounded by an AF cell-seeded random fibrous scaffold of polylactic acid reinforced polyglycolic acid [27, 28]. After 16 weeks of subcutaneous implantation, biochemical content of these disc-like constructs approached native levels, and, importantly, compressive mechanical properties increased with time . More recently, using a collagen-gel annular region along with an alginate NP region, both seeded with disc cells, this same group reported on the long term (>6 month) maintenance of disc height, reproduction of native tissue properties, and physiologic remodeling and integration of an engineered construct in a rat tail disc replacement model .
These promising studies highlight the potential for the engineering of a mechanically viable NP, AF, or whole disc structure. As an alternative to implantation of an immature construct (with in vivo maturation), new materials can be used to direct the formation of an organized tissue matching native disc structure and function. For example, using aligned nanofibrous scaffolds as a starting template, we demonstrated that a single annulus layer, with physiologic fiber organization, could be produced . When these oriented nanofibrous constructs were seeded with AF cells , constructs increased in tensile modulus with time and the orientation of collagen coincided with the scaffold fiber direction. Extending this work to consider the multi-lamellar hierarchy of the native AF, we next assembled MSC-seeded angle-ply bi-lamellar structures with a fiber orientations of ±30° in each layer . By 10 weeks, angle-ply bi-layers reached a modulus very close to the modulus of the native AF (~18 MPa). When sections across two fiber planes were viewed using polarized light microscopy, a multi-scale collagen architecture mirroring the cross-ply organization of the native AF was observed: two layers of aligned, opposing collagen. Such studies provided insight into the fundamental reinforcing effect of alternating directions in angle ply laminates, and may serve as a promising tissue engineering template for AF repair.
Further, these angle-ply laminate structures can be formed into disc-like angle-ply structure (DAPS) that replicate the multiscale architecture of the intervertebral disc, inclusive of a laminate AF region and a gelatinous NP region .
In vitro culture of such constructs showed that the mechanical characteristics of the disc under compression and torsion were qualitatively similar to native tissue, although lesser in magnitude, and increased with time in culture. Cells seeded into both AF and NP regions adopted morphologies that mirror those seen in native tissue, with rounded cells in the NP and more elongated cells in the AF regions. In the AF region, the collagenous matrix deposited followed the angle-ply configuration of the scaffold. While considerable advances have been made in disc tissue engineering, most notably the transplant of a mechanically functional disc-like analogue in vivo in a rodent model, there remain a number of hurdles to overcome before biologic disc replacement becomes a clinical reality. Advances in disc replacement in a small animal model will need to be evaluated in larger species, where diffusional and mechanical demands will be greater. Engineering for an inflamed environment, likely present in degenerating discs, will further complicate this transition, and novel materials that can address this scenario may be required.
Despite these limitations, lessons learned in the pursuit of a full biologic disc replacement will likely provide nearer term solutions for instances of NP degeneration or AF fracture. Along with these applications, new and minimally surgical approaches will need to be developed to ease clinical application. These advances will provide early stage treatment options that may slow disc degeneration, until such time as biologic substitutes become a clinical reality. Despite the remaining hurdles, progress in disc tissue engineering has been rapid and is already making an impact. These advances will continue to accelerate and will one day provide a paradigm shift in the treatment of disc degeneration, providing long term and functional solutions for what is today an intractable, debilitating, and widespread condition.
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This work was supported by the National Institutes of Health, the Department of Veterans’ Affairs, the US Department of Defense, and the Penn Center for Musculoskeletal Disorders.
Thanks for posting! Very interesting and hopeful for the future of reversing disc degeneration. Maybe not in the next couple of years (???) but clearly for the next generation
54 yr old retired beachbum
1986: Full rupture at L3-4, severe left foot drop, Laminectomy/chondrectomy 3 days after accident (successful)
1997-2000: reinjury but not typical disc symptoms
2000: 5 Prolotherapy treatments (successful)
2009-present: reinjury but prolotherapy treatments (8 total) have diminishing effect
|icrs, intervertebral disc, tissue engineering repair|
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