Annulus Fibrosus Repair

15  Annulus Fibrosus Repair


Olivia M. Torre, Michelle A. Cruz, Andrew C. Hecht, and James C. latridis


Abstract


This chapter describes the clinical need for annulus fibrosus (AF) repair as well as the state of the art in AF repair procedures and next-generation AF repair strategies that aim to improve upon currently available treatments. AF injury from herniation and degeneration can result in complications such as accelerated degeneration and prolonged chronic pain. Discectomy is the standard treatment for painful conditions associated with the ruptured AF from herniation, and is highly effective at reducing acute radicular pain; however, it does not promote repair and there is a risk of reherniation. AF closure devices can augment discectomy procedures by reducing the reherniation risk, but they do not promote tissue repair. AF repair research is broad and involves technologies including experimental biomaterials, drug and cellular-based therapies, and combination treatments. A key challenge is to design AF repair strategies that withstand complex loads on the spine while promoting integration and regeneration with the native tissue. Natural and synthetic biomaterials have been developed to mimic certain AF properties, and some show substantial promise for sealing AF defects. The most promising strategies to promote AF repair involve combinations of biological factors, cell delivery, and biomaterials. However, regulatory considerations hinder the translation of such complex strategies to clinical use. Several promising experimental strategies exist and require further material development and validation.


Keywords: annulus fibrosus, biomaterials, cell delivery, intervertebral disc, regeneration, repair


15.1  Historical and Clinical Perspective


The annulus fibrosus (AF) contains the highly pressurized nucleus pulposus (NP) in order to maintain intervertebral disc (IVD) height under the large spinal loads and deformations that occur during activities of daily life. Degenerative changes or traumatic injury can lead to herniation of NP tissue through defects in the AF. Unrepaired AF defects can directly result in debilitating painful conditions by leading to compression of adjacent nerve roots by herniated tissue,1,2 and can indirectly result in painful conditions by leading to accelerated IVD degeneration, which can predispose to biomechanical instability, chronic inflammation, and increased nociception.3,4 AF repair following herniation is challenging due to the limited self-healing capacity of the IVD and the need to withstand complex repetitive loading.5


Walter E. Dandy provided the first report of a lumbar IVD herniation in 1929, in which he observed the detachment of an IVD fragment and described the associated painful conditions related to the herniated material bulging into the spinal canal.6 Pain and disability from herniation was long-believed to be associated with extent of mechanical compression of the herniated tissue on the nerve root.7 However, clinical and scientific observations that nerve root–related pain gradually resolved without any change in the mechanical deformation implicated neural inflammation due to contact of the nerve with autologous NP tissue.8,9 Mixter and Barr described a procedure to relieve the painful conditions associated with IVD herniation in 1934, giving rise to the field of lumbar discectomy in which extruded NP tissue is removed.10 Since Mixter and Barr’s report, discectomy procedures have vastly improved to become less invasive with faster recovery times and improved patient outcomes. Discectomy is now the most commonly performed surgical procedure to alleviate low back and leg pain with 300,000 procedures performed yearly in the United States.11,12,13,14 However, discectomy procedures do not involve repairing the existing AF injury resulting from the herniation, and can enlarge the defect size in the process of removing herniated tissue (▶ Fig. 15.1). Sealing such large iatrogenic defects from discectomy poses distinct biological and mechanical challenges involving larger defects in a specific area. In contrast, defects resulting from degenerative changes with age may be smaller in size and in more locations. Furthermore, adjacent AF tissue quality impacts repair potential and ranges from high-quality tissue with good mechanical integrity (e.g., in younger patients with defects associated with injuries) to degenerated tissue of poorer mechanical integrity (e.g., in patients with herniation due to chronic degenerative conditions).



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Fig. 15.1 Intraoperative image of large annular defect after discectomy.


AF repair strategies include devices (sutures and implants), experimental biomaterials (sealants and scaffolds), biologics and cell-based therapies, and combinatorial strategies (▶ Fig. 15.2). The objectives of this chapter are to provide a summary of the current state of the art in AF repair techniques for defects resulting from herniation and subsequent discectomy procedures, and an overview of experimental biomaterial, biological, and cell-based strategies aiming to improve upon current treatment options.



15.2  Current Procedures for Annulus Fibrosus Repair


Discectomy procedures can afford superior clinical outcomes after a failure of nonoperative treatments for lumbar IVD herniation.14 However, the challenge of a microdiscectomy is to determine how much disc material needs to be removed. Typically, the loose or herniated pieces are removed and an annular defect remains. The more disc that is removed by the surgeon the greater the risk of degeneration, and if too little is removed the risk of reherniation is greater. Consequently, there is a balance between removing sufficient amounts of NP tissue to prevent reherniation and removing so much NP tissue that the remaining IVD is at risk for further injury to the end plates, faster rates of degeneration, IVD height loss, and subsequent pain at the same spinal level.15 The rate of reherniation, postsurgical pain, and recurrent pain at the same level of the discectomy is 5 to 25%,16,17,18,19,20 demonstrating an important clinical need to develop AF repair strategies. An ideal AF repair strategy would prevent reherniation, seal the remaining defects, and restore the mechanical behavior of the AF to a healthy level.5 However, current surgical treatment options for radicular pain associated with herniation do not offer effective repair strategies, and developing AF repair strategies remains an unmet clinical challenge.


15.2.1  Causes of Annulus Fibrosus Injury


The AF undergoes structural changes with degeneration, age, and pathological loading, and these changes include tears, fissures, and defects to the lamellar layers and can result in AF rupture and herniation.5,21 AF punctures, defects, and simulated discectomy procedures in healthy IVDs are known to accelerate IVD degeneration in animal models and organ culture.22,23,24,25,26,27 Although some clinical data suggest discectomy procedures result in accelerated IVD degeneration,28 it is difficult to separate effects of discectomy from degeneration that might have occurred at that spinal level due to existing herniation and AF damage.28


15.2.2  Currently Available Annulus Fibrosus Repair Strategies


Currently available AF repair strategies include suturing and implants, which focus on AF closure or prevention of reherniation (▶ Fig. 15.3), and several have been used in clinical trials (▶ Table 15.1). Suturing AF defects was a promising solution due to its simplicity; however, it was ineffective in restoring intradiscal pressure in animal models29 and suturing procedures are very challenging in the posterior AF region due to surrounding nerve roots. An improved suturing system is commercially available in Europe, and has offered slightly lower, but not significantly decreased, reherniation rates and no additional risk (Xclose, Anulex Technologies Inc., Minnetonka, MN).30 However, this technology was removed from the U.S. market. The PushLock knotless suture anchor, approved for rotator cuff repair, has been studied as a potential AF closure device31 however, this approach is suitable only for patients with sufficient tissue integrity of the ruptured AF and vertebral end plate, and is therefore only feasible for a small subset of patients. Barbed polyethylene annular closure device implants tested in goats in vivo demonstrated material deformation, end plate damage, and device expulsion after 6 weeks, presumably due to a mismatch in mechanical properties.32 The Barricaid (Intrinsic Therapeutics, Woburn, MA), is an implant for AF closure consisting of a titanium bone anchor and polymer mesh positioned in the annular defect, and shows promise for preventing reherniation and retaining IVD height.33,34,35



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Fig. 15.3 Devices for annulus fibrosus repair. (a) The Xclose (Anulex Technologies; Minnetonka, MN) modified suture system is approved for use in Europe.30 (b) The PushLock knotless suture anchor (Arthrex; Naples, FL), approved for rotator cuff repair, has been studied as an annular closure device.31 (c) Annular closure device implants have been tested in in vivo goat models.32 (d) The Barricaid annular closure device (Intrinsic Therapeutics; Woburn, MA) is approved for use in Europe.35


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Currently available devices and treatments do not seal defects in the AF or promote tissue regeneration, and have not demonstrated a capacity to restore biomechanical function. Next-generation AF repair techniques are under development using experimental biomaterials with greater biomimicry and with cell delivery that are likely to be important for long-term clinical success, yet many challenges exist.


15.2.3  Clinical Challenges of Annulus Fibrosus Repair


Designing a regenerative AF repair technique is highly challenging due to the clinical, biological, and mechanical demands and generally good success of current discectomy procedures.5 Pure biomimicry of the AF is challenging due to the complex hierarchical, multilamellar structure of the AF, whose structure and material properties depend on location in the IVD. The IVD is avascular with low cellularity, providing a limited innate healing response. Innate repair of the IVD is poorly understood and efforts to promote repair activity through cell delivery, protein delivery, and gene therapy require extensive further investigation. Furthermore, there is limited information on the native AF cell phenotype, making it more challenging to design cell therapies. Nevertheless, several biomaterials and cell-based therapies exist that show promise to address at least some of these challenges and improve AF repair.


15.3  Experimental Biomaterials


Next-generation AF repair strategies include experimental biomaterials for AF repair that are formed as hydrogels to serve as AF sealants or in fibrous forms to better mimic AF structure (▶ Fig. 15.4). Design criteria for AF sealants were previous proposed to be36 (1) strongly adhesive, (2) biocompatible, (3) able to withstand immediate repetitive loading, and (4) injectable for easy delivery at the time of surgery.



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Fig. 15.4 Experimental biomaterials for annulus fibrosus (AF) repair. (a) Injectable fibrin-genipin adhesive hydrogel.36 (b) High-density collagen cross-linked with riboflavin.37 (c) Composite BBG-poly(polycaprolactone-triol-malate) (PPCLM) construct seeded with rat chondrocytes.38 (d) Shape-memory porous alginate scaffolds for AF regeneration.39 (e) Electrospun polyurethane.40 (f) Lamellar silk.41 (g) Type II collagen-hyaluronic acid hydrogel.42 (h) PDLLA/Bioglass composite foam scaffold.43


Biomaterials for AF replacement further aim to match native AF biomechanical and/or biological properties. Although a biomaterial possessing all these design criteria has yet to be been identified, this active field of research has produced many promising candidates. Various experimental biomaterials show promise as parts of tissue-engineered AF repair strategies and include natural, synthetic, combined, and electrospun materials (▶ Table 15.2).


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15.3.1  Natural Biomaterials


Natural biomaterials such as fibrin,36,44,45,46 collagen,37,47,48,49,50 alginate39,51,52 and silk53 have been investigated for their use as injectable AF sealants with the goal of preventing reherniation following discectomy and providing mechanical stabilization. The primary advantages of natural biomaterials are high bio-compatibility and ability to maintain highly viable cellular populations and ability to be formed as injectable hydrogels. Natural biomaterials have been modified to improve their adhesion to native tissue, biocompatibility, mechanical properties, and injectability with varied success.


Fibrin is a natural protein involved in blood clotting that has been commercially available for use as glue in many orthopaedic surgeries. Fibrin was used for IVD repair with some success in a porcine model54 and early clinical trials.55 However, Phase III clinical trials of fibrin injection in patients with low back pain showed no significant differences in outcomes compared with saline injections44 (Clinical Trial ID: NCT01011816), suggesting fibrin alone is not a useful material for AF repair. Adding genipin, a natural compound extracted from gardenia fruit, cross-links fibrin (FibGen) and resulted in increased shear mechanical properties to match AF tissues, slower degradation times compared with fibrin, and high cell viability in vitro.45,46 FibGen was able to withstand over 14,000 cycles of repetitive compression loading, restore IVD height, and restore compressive mechanical properties in injured bovine IVDs ex vivo.36 FibGen matches many of the criteria for design of an AF repair material and remains a promising candidate as an AF sealant.


High-density collagen, a major extracellular matrix (ECM) component of the AF, cross-linked with riboflavin has shown cell infiltration from native tissue and promising short-term mechanical properties matching the undamaged IVD in an in vivo rat model.37,47 Atelocollagen honeycomb-shaped scaffolds seeded with mature rabbit AF cells and implanted in a rabbit IVD degeneration model promoted short-term maintenance of cell viability, IVD height, and proteoglycan production48,49,50; however, mechanical properties of the implants were not evaluated. Modified collagen biomaterials show promise as AF sealants due to their injectability and biocompatibility; however, they require further mechanical testing and validation in the long term in vivo.


Shape-memory porous alginate is capable of recovering its original geometry once rehydrated and has the potential for minimally invasive delivery; however, it has material behaviors substantially lower than native AF.39 Alginate composites with collagen and chitosan have demonstrated enhanced cell compatibility and proliferation capacity when compared with alginate alone, and also tunable porosity to promote tissue integration and biocompatibility.39,51,52 Whereas alginate-based biomaterials have promising adhesion, biocompatibility, and injectability, further mechanical testing is required to validate these materials as candidates for AF repair.

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May 30, 2018 | Posted by in NEUROSURGERY | Comments Off on Annulus Fibrosus Repair
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