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Use of Temporary Implantable Biomaterials to Reduce Leg Pain and Back Pain in Patients with Sciatica and Lumbar Disc Herniation

The principle etiology of leg pain (sciatica) from lumbar disc herniation is mechanical compression of the nerve root. Sciatica is reduced by decompression of the herniated disc, i.e., removing mechanical compression of the nerve root. Decompression surgery typically reduces sciatica more than lumbar back pain (LBP). Decompression surgery reduces mechanical compression of the nerve root. However, decompression surgery does not directly reduce sensitization of the sensory nerves in the epidural space and disc. In addition, sensory nerves in the annulus fibrosus and epidural space are not protected from topical interaction with pain mediators induced by decompression surgery. The secondary etiology of sciatica from lumbar disc herniation is sensitization of the nerve root. Sensitization of the nerve root results from a) mechanical compression, b) exposure to cellular pain mediators, and/or c) exposure to biochemical pain mediators. Although decompression surgery reduces nerve root compression, sensory nerve sensitization often persists. These observations are consistent with continued exposure of tissue in the epidural space, including the nerve root, to increased cellular and biochemical pain mediators following surgery. A potential contributor to lumbar back pain (LBP) is stimulation of sensory nerves in the annulus fibrosus by a) cellular pain mediators and/or b) biochemical pain mediators that accompany annular tears or disruption. Sensory fibers located in the outer one-third of the annulus fibrosus increase in number and depth as a result of disc herniation. The nucleus pulposus is comprised of material that can produce an autoimmune stimulation of the sensory nerves located in the annulus and epidural space leading to LBP. The sensory nerves of the annulus fibrosus and epidural space may be sensitized by topical exposure to cellular and biochemical pain mediators induced by lumbar surgery. Annulotomy or annular rupture allows the nucleus pulposus topical access to sensory nerve fibers, thereby leading to LBP. Coverage of the annulus and adjacent structures in the epidural space by absorbable viscoelastic gels appears to reduce LBP following surgery by protecting sensory fibers from cellular and biochemical pain mediators.


Introduction
Patients with sciatica and severe lumbar back pain (LBP) resulting from lumbar disc herniation comprise a clinically challenging subgroup of patients [1][2][3]. Appendix table 1 summarizes many of the clinical reports that have appeared throughout the medical literature over many years. Most recently, the large, multicenter, NIH-funded SPORT study confirmed that most patients with sciatica from a herniated lumbar disc also have lumbar back pain [4][5]. This review summarizes preclinical and clinical data that provide information regarding the source of LBP in these patients. A hypothesis is developed which may provide direction for the development of surgical procedures and locally applied devices to reduce the post operative LBP which often accompanies successful reduction of sciatic pain following removal of the herniated disc.
Many types of biomaterials have been implanted in the epidural space in an effort to reduce postoperative pain caused by scar formation. None of these have been integrated into lumbar spine surgery as standard practice due to the challenges presented by the biomaterials as well as the unique anatomical space. Massie et al. concluded that one potential mode of action for the reduction of pain following surgery with the use of viscoelastic gels is the decreased migration of inflammatory cells into the epidural space by the viscous environment of the gel [6]. Viscoelastic gels would provide a protective tissue coating that decreases fibrosis and shields the nociceptors present on the exposed sensory nerves from pain mediators. The utilization of a mechanical barrier that coats and separates tissues in the lumbar spine provides some measure of surface protection of the sensory nerve against inflammatory mediators that occur as a result of surgery as well as outpouring from the annulotomy site itself.
diZerega et al. reported on a modern biomaterial for adhesion prevention which can be formulated into a flowable, biologically inert, viscoelastic gel with tissue adherence appropriate for use in minimally invasive surgery [7]. The device coats surgically traumatized tissues and remains at the site of placement even in gravitationally dependent areas. The data demonstrate that polysaccharide gels that coat healing tissues protect the tissues from cellular and biochemical pain mediators and fibrotic bridges that lead to adhesions during the healing process. The results of these studies demonstrated that the gels separated tissues during healing, thereby reducing their interaction by the interposition of a barrier.

Sciatica
Decompression surgery for disc herniation typically improves sciatica more than lumbar back pain [4,8]. Sciatica is reduced by removing compression on the exiting root of the sciatic nerve. Decompression further reduces the sensitization of the nerve root to pain mediators by reducing inflammation caused by mechanical pain stimulation [9].
There are several sources of pain generation in disc injury involving an intervertebral disc that is degenerative, bulging, or protruding [10][11][12]. Disc herniation provides direct pressure by disc tissue on the nerve root. Mechanical compression of a nerve alone is not necessarily painful, however, if that nerve is inflamed (irritated, tender, swollen), it can produce severe pain with a small amount of mechanical compression. Nerve root compression is an important factor in generating inflammation and resultant sciatica [13][14][15]. When both nerve compression and inflammation around the nerve root are present, there is more nerve injury and pain perception than after either event alone [16,17].
Spinal nerve root compression does not cause sciatica in all circumstances because more than 50% of "normal," asymptomatic people who have disc prolapses compressing the nerve roots have no pain [18]. In symptomatic individuals, the nerves are sensitized to compression, probably by biochemical pain mediators [19]. The inflammatory response that occurs as a result of nerve root compression also affects the sensory components of the lower back including the sensory nerves of the adjacent soft tissue. The inflammatory process is believed to sensitize the nerve root to all incoming stimuli. In such a state, even minor mechanical stimulation of the nerve root can evoke severe back pain. These pain mediators interact topically with nociceptors. Limiting the direct interaction of pain mediators with nociceptors was shown to reduce pain in preclinical models [6,20].
The mechanical compression of the nerve root may also lead to a series of intraneural tissue reactions, including edema, demyelination, and fibrosis that sensitize the surface of the nerve to pain mediators [9,13,21-22]; or tether the nerve root to adjacent tissues [23][24]. Mechanical compression increases microvascular permeability of the endoneural capillaries resulting in inflammation within the nerve root. Sensitizing the nerve root by topical exposure to pain mediators contributes to the pathogenesis of sciatica [13].

Lumbar Back Pain
The intervertebral disc is the main source of lumbar back pain (LBP). Intraoperative findings under local anesthesia showed that LBP was reproduced by stimulation of the outer annulus or the posterior longitudinal ligament (locations of sensory neurons). In contrast, sciatica was induced by mechanical stimulation of nerve roots [25][26][27][28][29][30].
The reduction in LBP that follows decompression surgery results from reduced production of pain mediators (biochemical as well as cellular) in the epidural space (disc, adjacent soft tissues, nerve root), which reduces stimulation of nociceptors in the sensory nerve fibers of the annulus and adjacent soft tissues. Decompression surgery also reduces the sensitization of these sensory nerve fibers to stimulation by pain mediators [31].
Microtrauma damages the annulus fibrosus, allowing blood vessels and nerves a deeper penetration into the annulus fibrosus [21]. Increased vascular and neural in-growth are seen in discs associated with LBP. Malinsky demonstrated a variety of free nerve endings and some button-like terminals exist in the outer few layers of the lumbar annulus and noted partially and fully encapsulated mechanoreceptors confined to the annular surface [32][33]. These free nerve endings contribute to pain transmission from the disc producing LBP [32]. Furthermore, the concentration of nerves and blood vessels in the annulus increases with age [34].
Free nerve endings are present in the annulus fibrosus and epidural space (ligaments, nerve roots and muscles). In patients with sciatica caused by disc herniation, reports of LBP preceding sciatic pain are common. Patients with severe LBP associated with disc herniation and sciatica have greater density of sensory nerves in the annulus fibrosus and epidural space than patients with less severe LBP [13,16,21,35-39], which results in sensitization of more sensory nerves and additional LBP following decompression surgery. It has been suggested that this pain may be caused by topical stimulation of nerve endings in the annulus fibrosus as a result of an annular tear and/or herniation and later by inflammation associated with extrusion of the nucleus pulposus. Chemical sensitization of sensory nerve fibers of the disc is induced by inflammation caused initially by disc herniation and later by the trauma of surgical decompression. Removing the herniating portion of the disc and/or the residual nucleus pulposus reduces inflammation in the epidural space [10,12,40-42]. Trauma to an intervertebral disc may damage disc components, resulting in the production of irritants (biochemical mediators), which may drain either into the spinal canal, irritating nerves, or into the vertebral body, setting up an autoimmune reaction resulting in LBP [10,12,21,43-44].
Biochemical mediators of pain are present in disc herniation tissue [10]. Axonal injuries and inflammatory stimulation of nociceptors alter nerve root excitability and thereby play an important role in LBP [45][46]. Local production of chemokines within the epidural space also contributes to LBP [47].
A number of experimental studies demonstrated the negative affects of disc tissue, and in particular the nucleus pulposus, on nerve roots [48][49][50][51][52][53][54][55]. When the substance of the nucleus pulposus comes into contact with sensory nerves of the epidural tissues including the outer annulus it: 1) induces degeneration of nerve fibers; 2) increases discharge of nerve fibers; 3) attracts inflammatory cells (cellular mediators of pain) and; 4) induces increased intraneural capillary permeability.

Lumbar Disc: Anatomy
In order to understand how pain is generated in the disc and epidural space, a brief review of the disc, epidural space and associated neuroanatomy is useful. The disc is composed of a central nucleus pulposus surrounded peripherally by the annulus fibrosus ( Figure 1). In normal young adults, the nucleus is a semi-fluid mass of mucoid material (glycosaminoglycans, proteoglycans, and collagen). The nucleus is composed of approximately 70-90% water in a young healthy disc, but this percentage generally decreases with age [9]. The annulus fibrosus consists of 10-20 concentric collagen fiber layers that surround the nucleus. The layers are arranged in alternating orientation of parallel fibers.

Figure 1.
A sectional view of a normal lumbar disc. Note the locations of the nucleus pulposus, the vertebral end plate and the annulus fibrosus. The intervertebral lumbar disc is typically 4cm wide and 7-10 mm thick (adapted from Raj et al. [34]). The interior of the disc including the nucleus pulposus is avascular.
The vertebral endplate is a thin layer of cartilage located between the vertebral body and the intervertebral disc. Although normally composed of both hyaline and fibrocartilage in youth, older end plates are virtually entirely fibrocartilage exposing the sensory fibers that course through these areas to topical stimulation. The intervertebral disc is the largest avascular structure in the body. As a result, exposure of epidural tissues to the nucleus pulposus produces an autoimmune response increasing the concentration of cellular and biochemical pain mediators.
The central component to any injury involving the lumbosacral discs is the natural aging process and/or trauma [56]. Disc aging typically involves circumferential tears or fissures in the outer annulus. These changes are thought to result from repetitive microtrauma. Brown et al. and Ohtori et al. reported that, in patients with lumbar back pain (LBP), there were increases in the density of sensory nerve fibers in the endplates and defects in the endplate cartilage, strongly suggesting that the endplates and vertebral bodies were sources of pain [57][58].
Sensory nerves in the disc often accompany blood vessels present in the longitudinal ligaments adjacent to the disc, but they can also occur independently, arising as branches of the sinuvertebral nerve or derived from the ventral rami or gray rami communicans [34] (Figure 2). The ventral rami and gray rami communicans form a ventral plexus that supplies the anterior and lateral aspects of the annulus and the anterior longitudinal ligament. The posterior annulus fibrosus and the posterior longitudinal ligament are innervated by the sinuvertebral nerve (contributes branches to the dorsal plexus), which consists of sensory fibers. Each sinuvertebral nerve supplies the disc at its level of entry into the vertebral canal [59-60]. Most of the nerve fibers are sensory in origin and are involved in nociception [33,39,60-62].

Figure 2.
The course of the sinu-vertebral nerve (yellow), which innervates the posterolateral region of the disc (blue). The nerve exits from the nerve root and enters the vertebral foramen, where it divides into a major ascending and a lesser descending branch (adapted from Raj et al. [34]).
The anterior longitudinal ligament also receives sensory innervation from branches that originate in the nerve root. The posterior longitudinal ligament (PLL) is richly innervated by nociceptive fibers from the ascending branch of the sinuvertebral nerve ( Figure 3). These nerves also provide sensory innervation of the adjacent outer layers of the annulus fibrosus [34]. Herniation and rupture of the disc/longitudinal ligament typically leads to exposure of the epidural space to pain mediators.

Sensory Innervation of the Disc
In 1949, Herlihy reported that direct innervation of the intervertebral disc could lead to intrinsic pain stimulation at the disc [59,63]. Subsequently, multiple studies conclusively demonstrated that the intervertebral disc is innervated [59,64]. In a normal disc, the outer one third of the annulus is innervated; the inner two thirds of the annulus and the nucleus pulposus receive no innervation [59]. A high proportion of nociceptive nerve fibers arising from the annulus of the lumbar discs pass through the sympathetic trunks as sympathetic sensory afferents. These pain receptors are sensitized by changes in external pressure (mechanoreceptors) or inflammatory irritation [22,65-67].
The lumbar intervertebral disc is innervated by the sinuvertebral nerves ( Figure 3 In contrast, disc material obtained from patients with LBP showed deeper in-growth of blood vessels and nerves. Freemont examined the innervation of the inner disc using 46 biopsy samples (30 from levels with pain and 16 from levels with no pain) [21]. Innervation of the inner disc was observed more frequently in painful discs than in asymptomatic discs. They further demonstrated the presence of nerve fibers in painful discs demonstrating that nociceptive nerve fibers were growing into the painful disc. Nerve in-growth into the inner disc follows the development of fenestrations resulting from trauma and/or aging (Figure 4). These sensory afferents, which can transmit pain from the disc itself, contribute to LBP with herniation ( Figure 5).
The pain receptors of the intervertebral discs are nociceptors, which are activated under inflammatory conditions when their surface comes into contact with biochemical and cellular mediators of pain, which lead to pain perception. Inflammatory changes may cause the silent nociceptors to become responsive to mechanical stimuli, and this nociceptive information is perceived as LBP [27,80]. Takebayashi found that the lumbar intervertebral discs were not responsive to mechanical stimulation under normal conditions, but once inflamed by the topical application of biochemical pain mediators, mechanically insensitive afferents responded to mechanical stimulation [81].   . Schematic representation of a mechanism for LBP. An annular rupture leads to extrusion of the nucleus pulposus (pink) outside annulus fibrosus (blue), which induces nerve injury and nerve in-growth into the disc (yellow). Under inflammatory conditions which may occur following surgery, nerve growth factor (NGF) is induced in the disc and acts on the nerve root (DRG) through the peripheral terminals in the disc. Disc-innervating neurons have a high sensitivity to NGF. NGF may promote nerve in-growth into the disc, sensitize DRG neurons, and cause neuronal sprouting into the dorsal horn (adapted from Takahashi et al. [38]).

Sensory Innervation of the Epidural Space
The soft tissues (ligaments, muscles) and nerve root adjacent to the disc contribute to lumbar back pain (LBP) by stimulation of sensory nerves [65,86]. Rupture of the posterior longitudinal ligament and extrusion of nucleus pulposus into the epidural space ( Figure 5) evokes an autoimmune reaction and infiltration of cellular pain mediators [41,[87][88][89][90]. Chemical mediators throughout the epidural space (especially from the intervertebral disc itself) are a significant source of both LBP and sciatica as well as sensitization of sensory nerves [11,91-93]. Burke et al. found that patients with severe LBP generally had higher levels of inflammatory mediators than those patients with lower levels of disc pain [10].

Sensitization of Sensory Nerves
Mechanical stimuli which are normally innocuous to disc nociceptors can generate an amplified response which has been termed 'peripheral sensitization' Exposure of epidural tissue to inflammatory cytokines from the disc nucleus results in both nerve sensitization [12] and nerve injury [42,84]. Franson showed that human PLA2 concentration in the intervertebral disc are 20-10,000 times higher than the PLA2 found in other human tissues [99]. A wide variety of pain mediators that come in contact with the nerve root during and after disc surgery can sensitize neural tissue to postoperative pain and neurological symptoms [10-12,19,100] Increase in sensory nerve excitability that can occur following decompression surgery often prolongs sensory nerve sensitization resulting in pain and hyperalgesia long after the surgical procedure [101].
The combination of mechanical compression (mass effect of herniated disc) and chemical irritation by cellular and biochemical mediators (inflammation around nerve root) induces more LBP than either factor alone [16]. As reviewed by Cohen et al., the concept of chemical sensitization may explain the contrasting responses between LBP and asymptomatic discs. Tumor necrosis factor-α (TNF-α) is expressed in the nucleus pulposus and plays a role in generating sciatic pain in patients with disc herniation [102,103,104]. Interleukin-1β (IL-1 β), which is produced in tissues involved in disc herniation, has the capacity to produce hyperalgesia. Also, NGF, which is up regulated by such mediators, has a sensitizing effect on nerve fibers. The levels of inflammatory mediators are higher in painful discs than in asymptomatic discs, suggesting that their interaction with tissues in the epidural space would produce LBP [10,105].

Post Operative Pain
Surgical dissection and retraction cause nerve root trauma and cellular injury, expose neural tissues to blood and disc substance (nucleus pulposus), filling the epidural space with cellular and biochemical pain mediators. These lead to nerve root irritation, inflammation and fibrin production each of which can trigger additional inflammation, trauma, nerve root compression or tethering and sensory sensitization. Mechanical deformation of nerve tissue resulting from surgical dissection also contributes to prolonged postoperative lumbar back pain (LBP). Laminectomies may also induce an increase in the density of nociceptive neurons in the lumbar disc ascribable to axonal sprouting of fine sensory nerve fibers. Neuronal outgrowth of nociceptive afferents is associated with LBP after lumbar surgery [106]. The leaking "chemical soup" within the nucleus pulposus contains pain mediators that stimulate sensory fibers following annulotomy. Neuropeptides released from peripheral endings of nociceptive afferents are also inflammatory mediators and pain generators [107].

Pain Mediators during Herniation and Following Decompression Surgery
A large number of cells (principally inflammatory) and biochemicals are present in the disc and epidural space during herniation that are not present in normal disc tissue. They have been shown to interact with nociception and sensory nerve transmission and are collectively referred to here as "pain mediators". The concentration of these pain mediators increase in these tissues following surgery. As a result, even though mechanical decompression is completed, pain often continues, especially lumbar back pain (LBP) (Appendix Table 2).

Neutrophils
Inflammatory cells at the surgical site increase in both number and activity. During and immediately following surgical injury, neutrophils enter the surgical field in large numbers. An increase in neutrophil number or concentration within the surgical site can contribute to pain. Neutrophils release a number of products that cause tissue destruction and continued inflammation (oxygen radicals, protease, etc.) that contribute to pain through topical interaction with sensory fibers and nociceptors [11,21,82,94-95,108].

Macrophages
The second cell type to enter the epidural space after surgery is monocytes/macrophages. These cells secrete oxygen free-radicals, along with pro-inflammatory cytokines. Gronblad et al.

Biochemical Pain Mediators Identified in the Epidural Space in Patients with LBP
A large number of biochemical pain mediators have been identified in the disc and epidural space that contribute to LBP following decompression surgery (Appendix table 2  Burke et al. confirmed and extended these observations by quantitating proinflammatory biochemical pain mediators (IL-6, IL-8 and PGE2) in disc tissue obtained from patients undergoing lumbar surgery for sciatica and LBP ( Figure 6) [10]. Those patients with LBP (n = 20) had significantly higher concentrations of biochemical pain mediators than patients with only sciatica (n = 63). Hyperalgesia is induced in an innervated nucleus pulposus by cellular and biochemical pain mediators. The exposure of the nucleus pulposus to the outer annulus fibrosus induces nerve injury. Hyperalgesic responses can be induced by contact of the nociceptors of sensory nerves with nucleus pulposus that signal LBP directly from the disc and epidural space [38].

Annular Leakage and Pain Sensitization
Disc herniation is typically preceded by one or more attacks of acute lumbar back pain (LBP) . LBP may also occur when there is internal disruption of annular fibers but no tearing of the outer layers of the annulus. In this situation, there is local injury to the sensory fibers of the outer one-third of the annulus as well as leakage of the nucleus pulposus into the epidural space. Kayama et al. found that incision of the annulus fibrosus without disc herniation, but with a slow leakage of nucleus pulposus through the incision, induced significant pain and nerve damage in a dog model [37]. These preclinical studies supported their clinical experience that patients suffer from more severe pain when nucleus pulposus is communicating with the epidural space compared with those in whom the herniated nucleus pulposus is contained within the annulus fibrosus [44].
Materials that leak from annular tears induce single level nerve root pain or multi-level nerve root pain through diffusion. Peng et al. found that the nerve injury caused by the combination of mechanical compression (mass effect of herniated nucleus pulposus) and chemical irritation (inflammation around the nerve root or perineural inflammation) may induce more nerve root injury than each factor alone ( Figure 7) [44]. The nerve root becomes sensitized by nucleus pulposus material that reaches the epidural space through annular tears [11,37,50-53,132-135]. Since the pain threshold has been lowered, the additional mechanical compression on the nerve root may induce an excruciating pain due to the presence of chemical radiculitis resulting from topical exposure of sensory fibers to chemical mediators [44].

Sensitization by Fibrosis
Fibrosis has received considerable attention as a contributor to sciatica and lumbar back pain (LBP) following decompression surgery. Kuslich et al. found that spinal nerve roots encased in perineural fibrosis were very sensitive to external stimulation in patients with prior laminectomies undergoing repeat procedures under minimal anesthesia [26]. Neuropathic changes in the spinal sensory potential correlated with postoperative perineural fibrosis in a rat model of laminotomy up to 3 months following surgery [136]. These observations provide direct evidence of nerve root sensitization to pain by perineural fibrosis. While epidural fibrosis commonly results following surgical intervention of the spine, leakage of disc material into the epidural space following an annular tear or surgical intervention can also result in the formation of epidural fibrosis [137][138][139][140][141][142][143][144][145][146][147].
Fransen evaluated the reduction of epidural fibrosis in a group of 396 patients following single level disc herniation and presenting with sciatica often associated with LBP [148][149]. All subjects were operated upon by the same surgeon in the same institution (Clinique du Parc Léopold, Brussels, Belgium) between January 1st 2003 and December 31st 2005. Upon completion of a conventional microdiscectomy, in all patients, the decompressed nerve root and epidural space including the annulus fibrosus were systematically covered with a gel composed of carboxymethylcellulose (CMC) and polyethylene oxide (PEO). Five (5) patients needed reoperations for recurrent herniation, two (2) after less than a week, one after one month, and two (2) within the first year after surgery. In perioperative assessment of the reoperations, there was little or no epidural fibrosis. This facilitated dissection and separation of the nerve root from surrounding tissues.

Epidural Adhesions
Adhesions themselves are not painful. Epidural fibrosis and subsequent tethering of the nerve root to the disc or pedicle (and thereby compression), may contribute to post-surgical sciatica and lumbar back pain (LBP). However, results of clinical outcome studies attempting to correlate adhesion formation with pain have not been consistent [150][151][152]. Most patients with epidural fibrosis do not develop symptomatic complaints [153]. However, fibrous entrapment of nerve roots may cause sciatica as demonstrated by their release, resulting in immediate relief from sciatica [154]. The pain is thought to result from entrapment of the nerve root by fibrosis resulting in enhanced sensitization in contrast to tethering.
Ido reported seven (7) patients with fibrous adhesive entrapment of lumbosacral nerve roots as a cause of sciatica. Radiographic findings (MRI, myelography and CT myelography) of the patients were negative (no disc herniation or nerve root compression). All seven patients complained of sciatica accompanied by LBP. Differential nerve blocks were effective in relieving sciatica and LBP in these patients. Surgical procedures resulted in the release of the nerve root and creation of space around it. All seven patients experienced complete relief from sciatic pain and LBP immediately after the fibrous sheath was released. During the average follow-up period of 7 years and 2 months, no recurrence of sciatic pain accompanied by LBP was observed [154].

Protection of Epidural Sensory Nerves by Gels
Reduction in fibrin deposition would reduce nerve root entrapment and reduce sensitization to pain [154]. Coating of tissues in the epidural space also reduces postoperative pain following lumbar disc surgery by reducing the interaction of sensory nerves in the lumbar disc and epidural space from cellular and biochemical pain mediators. To be effective, such barrier gels need to be present for a short time to reduce exposure of damaged tissue to macrophages and other inflammatory cells known to stimulate painful nociceptors, and to provide mediators that trigger the development of fibrosis by attracting fibroblasts (Figure 8).
It has been shown in preclinical and clinical studies that coverage of the nerve root with a polyanionic polysaccharide viscoelastic gel such hyaluronic acid (HA), or carboxymethylcellulose (CMC) /polyethylene oxide (PEO) reduces pain and symptoms [155]. Healon® (HA) and Oxiplex® (CMC/PEO) are two such high-molecular-weight polysaccharide gels. The concentration of solids in polysaccharide formulations appears to enhance the mucoadherance and viscoelastic properties that improve tissue coating [7,20, [156][157]. A number of preclinical studies demonstrated that HA gel reduces pain and the presence of cellular as well as biochemical pain mediators in rat and canine laminectomy models [6,20, [158][159][160][161][162]. Hyaluronic acid gel was also shown to inhibit macrophage migration into the epidural space and release of biochemical pain mediators in the wounds of animals following laminectomy [20,159]. The investigators at the University of California San Diego described a laminectomy model that resulted in a heightened sensitivity to pain [20,158]. Pain reduction by polysaccharide treatment after laminectomy and disc injury in a rat model resulted from reduction in the concentration of the cytokines and inflammatory cell infiltrates that would otherwise occur around the nerve root and the epidural space. . Coverage of the annulus and adjacent structures in the epidural space by absorbable viscoelastic gels appears to reduce LBP following surgery by protecting sensory fibers from cellular and biochemical pain mediators. For example, carboxymethylcellulose (CMC) provides tissue coating which protects the surfaces of epidural tissues from topical interaction with cellular and biochemical pain mediators (B); polyethylene oxide (PEO) interacts with the biochemical pain mediators (especially proteins) reducing their topical access to sensory nerves of the annulus fibrosus and epidural space [7]. Gels which protect tissues during healing, thereby reducing their interaction by the interposition of a temporary viscoelastic gel, should provide a useful strategy to reduce both back and leg pain following lumbar disc surgery.
Massie et al. concluded that one mode of action for the reduction of pain following surgery with the use of viscoelastic gels is the decreased migration of inflammatory cells into the epidural space by the viscous environment of the gel [6]. Viscoelastic gels would provide a protective tissue coating that decreases fibrosis and shields the nociceptors present on the exposed sensory nerves from pain mediators. The utilization of a mechanical barrier that coats and separates tissues in the lumbar spine provides some measure of surface protection of the sensory nerve against inflammatory mediators that occur as a result of surgery as well as outpouring from the annulotomy site itself. In this mode of action, the tissue coating properties, molecular weight, concentration, and the rheology of the viscoelastic gel are important [7, [163][164].
The components of Oxiplex (carboxymethylcellulose, or CMC, and polyethylene oxide, or PEO) separate tissue by providing a viscous coating that prevents migration and attachment of cellular and biochemical pain mediators to covered tissues cells [165][166][167][168][169]. The CMC component allows for gel adherence to tissues [157,[170][171]. The PEO component prevents protein deposition [172][173][174][175][176] on the surface of covered tissues. The combination of CMC and PEO allows the gel to remain at the site of application for a period of time, providing a mechanical barrier to protein and cell deposition that could otherwise lead to pain and adhesion formation during the healing process [156,[177][178].
The data demonstrate that polysaccharide gels that coat healing tissues can protect tissues from cellular and biochemical pain mediators and fibrotic bridges that lead to adhesions during the healing process. Coverage of the annulus and adjacent structures in the epidural space by absorbable viscoelastic gels appears to reduce LBP following surgery by protecting sensory fibers from cellular and biochemical pain mediators. The results of these studies demonstrate that gels which protect tissues during healing, thereby reducing their interaction by the interposition of a temporary viscoelastic gel, should provide a useful strategy to reduce both back and leg pain following lumbar disc surgery. Appendix Table 2. Biochemical pain mediators.  Central nervous system. Walsh [194] FGF2 or FGFb Fibroblast growth factor, basic  Involved in angiogenesis, wound healing, and embryonic development.  Almost all of the disc-innervating neurons are NGF-sensitive type and axonal injury or stimulus to the dorsal root ganglion may cause disc innervation.  Central nervous system. Aoki [195] GM  IL-1 treatment has been linked to increases in proinflammatory factor production via activation of NF-κβ, a major regulator of inflammatory cytokine-inducible genes.

Mediator
 IL-1 pretreatment has been shown to stimulate the production of the reactive oxygen species nitric oxide (NO) and increased synthesis of nitric oxide synthase (NOS).
 IL-1 has been shown to decrease proteoglycan synthesis and increase matrix catabolism via up regulated matrix metalloproteases (MMP) activity in osteoarthritic cartilage.
 Stimulates degradation of the extracellular matrix and induce changes to the biochemical properties of the discs, notably the loss of proteoglycans.  Potent pain generating mediator.
 Plays an active role in inflammation and immunology.
 IL-6 is the primary chemical mediator involved in bone inflammation and bone pain.
 Chemoattractant for neutrophils and T cells.
 Secreted by macrophages, lymphocytes, epithelial cells, and endothelial cells.
 Inhibits cytokine production, promotes B cell proliferation and antibody production, suppresses cellular immunity, mast cell growth.
 May play a role in the collateral sprouting of sensory axons, neural survival and regulation of nociceptive sensory neurons.
 Promotes nerve in-growth in to the intervertebral disc (IVD).
 NGF has been reported to be synthesized and released from innervated target tissues and to induce nerve in-growth in the target tissue.
 Directly modulates the function of nociceptive sensory neurons, resulting in pathological pain.
 May contribute to tissue repair.
 Inflammatory mediator by proliferation and/or activation of lymphocytes, eosinophiles, or mast cells.
 NGF produced by the intervertebral disc (IVD) cells, or by repair tissue, may sensitize these NGF-sensitive neurons, possibly resulting in discogenic pain.
 NGF expression level to cytokines may be dependent on the grade of disc degeneration.
 Expression of TrkA in IVD cells may suggest that NGF can affect IVD cells in a paracrine fashion, such as by the induction of transforming growth factor β, or by preventing apoptosis.
 The majority of disc innervating dorsal root ganglion neurons were NGF-sensitive neurons (rat model).    Autocrine regulator of fibroblast collagen synthesis and contraction.
 Has been shown to decrease proteoglycan synthesis and increase matrix catabolism via up regulated matrix metalloproteases (MMP) activity in osteoarthritic cartilage.
 Enhanced or maintained production of NO by annular cells may be desirable because NO is an autocrine regulator of fibroblast collagen synthesis and contraction and may therefore enhance wound healing.
 Glucosamine can reduce production of NO by nucleus cells but not annulus cells.
 Produced by nucleus pulposus cells and annulus fibrosis cells.

24]
 PGE2 is a direct vasodilator and it inhibits the release of noradrenaline from sympathetic nerve terminals.
 Sensitize spinal neurons to pain.
 Secreted in microvessels by the endothelium.

Weiler [126]
 PGE2 has been shown to decrease proteoglycan synthesis and increase matrix catabolism via up regulated MMP activity in osteoarthric cartilage.
 Glucosamine can reduce production of PEG2 by nucleus cells but not annulus cells.
 Regulated by phosphorylation and calcium concentrations.

Weiler [126]
Appendix  Provides a strong inhibitory signal to nitric oxide synthase (NOS).

Abe [40]
 TNF-α is expressed in the human degenerated intervertebral disc, especially in symptomatic discs.
 TNF-α is thought to be involved in the mechanism of nucleus pulposus-induced nerve root injury.
 TNF inhibitors (etanercept and infliximab) have been shown to be effective in preventing pathologic changes in nucleus pulposus-induced nerve injury. Or mechanical and thermal hyperplasia.
 On the other hand, and in vitro study showed that TNF-α inhibited axonal growth of dorsal root ganglion (DRG) neurons cultured as an organ culture.
 It is speculated that TNF-α secreted from pathologic discs can injure adjacent dorsal root ganglions (DRG) and also induce nerve in-growth from the injured dorsal root ganglions into the discs.
Aoki [195]   Appendix  Synthesized as a precursor protein that is proteolytically processed at the cellular surface via the TNF-α converting enzyme (TACE).  An important cytokine in nerve root injury because it is known to be neurotoxic and to induce axonal and myelin injury, intravascular coagulation and increased vascular permeability.
 Synthesized in the nuclear and anular disc regions.
 Change in proteoglycan content of degenerated discs has been suggested to be a contributing factor in IVD innervation.

Neurotransmitters (Receptors) AMPA
Alpha-amino-3hydroxy-5-methyl-4isoxazolepropionic acid  A compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.
 An ionotropic receptor for glutamate.
 Contributes to postsynaptic action.
 Repetitive small afferent input (as that which occurs after tissue injury) will evoke spinal glutamate release.  Yaksh [197] Glutamate Glutamate  Glutamate is stored in vesicles at chemical synapses. Nerve impulses trigger release of glutamate from the pre-synaptic cell. In the opposing post-synaptic cell, glutamate receptors, such as the n-methyl-D-aspartate (NMDA) receptor, bind glutamate and are activated.
 Most abundant excitatory neurotransmitter in the mammalian nervous system.
 Carboxylate anions or salts of glutamic acid.