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Fragmentation to Epidural Space: First Documented Complication of Gelstix(TM.)

  • Başkent University Adana Research and Education Hospital
  • Ministry Of Health Turkey

Abstract and Figures

The knowledge of minimal invasive spinal surgery has increased greatly in recent years. A current issue is the hydrogel implant inserted through nucleus pulposus. In this paper we present a case in which the hydrogel implant was found to be fragmented into the spinal canal at follow up. The patient was a 40-year-old female. She was examined at another clinic because of low back pain about four months ago, and a hydrogel implant was inserted at the L5-S1 level. She was admitted to our clinic due to severe radicular pain. Magnetic resonance imaging (MRI) showed a posterolateral annular tear only and she was explored microneurosurgically as she did not benefit from a foraminal injection. A fragmented hydrogel implant that compressed the spinal root was seen peroperatively and it was excised. Postoperatively the radicular complaints of the patient disappeared and she was discharged with total recovery. Although rare, complications causing compression of neural structures can be seen after placing implants into the disc. In this case, the assessment of the patient according to the clinical presentation and microsurgical exploration if necessary are important.
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Case Report
Turk Neurosurg 2014, Vol: 24, No: 4, 602-605602
Receved: 25.09.2013 / Accepted: 22.10.2013
DOI: 10.5137/1019-5149.JTN.9328-13.1
The knowledge of mnmal nvasve spnal surgery has ncreased greatly n recent years. A current ssue s the hydrogel mplant nserted through
nucleus pulposus. In ths paper we present a case n whch the hydrogel mplant was found to be fragmented nto the spnal canal at follow
up. The patent was a 40-year-old female. She was examned at another clnc because of low back pan about four months ago, and a hydrogel
mplant was nserted at the L5-S1 level. She was admtted to our clnc due to severe radcular pan. Magnetc resonance magng (MRI) showed
a posterolateral annular tear only and she was explored mcroneurosurgcally as she dd not beneft from a foramnal njecton. A fragmented
hydrogel mplant that compressed the spnal root was seen peroperatvely and t was excsed. Postoperatvely the radcular complants of the
patent dsappeared and she was dscharged wth total recovery. Although rare, complcatons causng compresson of neural structures can
be seen after placng mplants nto the dsc. In ths case, the assessment of the patent accordng to the clncal presentaton and mcrosurgcal
exploraton f necessary are mportant.
KEywORDS: Gelstx
, Epdural space, Fragmentaton
Son yıllarda mnmal nvazv spnal cerrahde büyük blg brkm kazanılmıştır. Güncel br konu da nükleus çne yerleştrlen hdrojel
mplantlarıdır. Bu çalışmada daha önce başka br klnkte hdrojel mplantı konulan ancak takbnde mplantı spnal kanala fragmante olan
br olgumuzu sunmak stedk. Kırk yaşında kadın hasta yaklaşık dört ay önce başka br klnkte bel ağrısı nedenyle tetkk edlmş ve L5-S1
sevyesne hdrojel mplantı konulmuş. Hastanın şddetl radküler ağrısı olması üzerne klnğmze başvurdu. Sol bacağında yaklaşık 10
derecede Laseque test müspetlğ saptanan hasta tetkk edld. Manyetk rezonans ncelemesnde sadece sol L5-S1 posterolateral annuler
yırtık saptanan ve foramnal enjeksyondan rahatlamayan hasta mkroşrürjkal teknkle eksplore edld. Peroperatf zlemde spnal kanala
bası yapan fragmante hdrojel mplantı görüldü ve eksze edld. Post-operatf radküler yakınması geçen hasta şfa le taburcu edld. Dsk ç
mplant yerleştrlmes sonrasında nadr de olsa nöral yapıları basılayablecek komplkasyonlar görüleblmektedr. Bu durumda hastanın klnk
durumuna göre değerlendrlmes ve gerekyorsa mkroşrurjkal olarak eksplorasyonu önemldr.
, Epdural aralık, Fragmantasyon
Correspondng Author: Emre DURDAG / E-mail:
, Omer AYDEN
, ıbrahim Burak ATCı
Elazig Education and Research Hospital, Department of Neurosurgery, Elazig
Private Medical Park Hospital, Department of Neurosurgery, Elazig
Presented in: 27th Annual Congress of Turkish Neurosurgical Society, poster presentation, 12-16 April 2013, Antalya, Turkey.
Fragmentaton to Epdural Space: Frst Documented
Complcaton of Gelstx
Epidural Mesafeye Fragmantasyon: Gelstix
’in Dökümante Edilen İlk
Low back pain is the second most frequent cause of work
loss, and its global prevalence in the 20-50 years age group
is 60% to 80% (3, 4). This pain usually ceases but can become
chronic. The most common cause of chronic low back pain
is degenerative disc disease (DDD), and environmental
and genetic factors are accused. There are many studies
related to DDD. In the degeneration process of the disc, it
is proven that decline of pH in the disc and deterioration of
disc perfusion together with impairment of type-2 collagen
formation occurs and leads to diminished water content in
the nucleus. This is followed by increased formation of type-1
collagen. The disc content becomes harder and inexible, and
neovascularization and reinnervation occurs in the annulus
Treatment options include conservative and surgical
approaches. Increased knowledge on DDD pathophysiology
has accelerated the development of some minimally invasive
percutaneous procedures that can aect degenerative
process positively. Application of hydrogel implants to
increase the amount of water in the disc space has become
popular (3,4,5). In this article, we would like to present the rst
known complication of a hydrogel implant.
A 40-year-old female patient was examined after low back
pain and severe radicular pain in her left leg. Her medical
history was unremarkable except insertion of a hydrogel
implant with the discography technique at the L5-S1 level at
another hospital four months ago (Figure 1). She claimed that
Presented in: XXII. Annual Scientific Congress of the Turkish Neurosurgical Society,
18-22 April 2008, Antalya, Turkey.
Turk Neurosurg 2014, Vol: 24, No: 4, 602-605 603
Durdag E. et al: Fragmentation of Gelstix
to Epidural Space
she did not benet from the procedure and was experiencing
low back pain after surgery. Her neurological examination
revealed a positive Laseque test in her left leg. There was
signicant weakness in plantar extension of the foot and
diminished Achilles reex. Magnetic resonance imaging
(MRI) was normal except for a left paracentral hyperintense
zone at the L5-S1 level. A trial of foraminal steroids provided
no benet. Surgical exploration was decided on due to
the severe nature of the pain and absence of a signicant
radiological evidence that would explain it, and the patient
was underwent microsurgery. Peroperatively, a hydrogel
implant protruding from the annular tear was observed. The
left S1 root was signicantly compressed by the implant.
The implant was excised in two fragments. Pain ceased
immediately postoperatively and the patient was discharged
without any problems (Figure 2AD).
DDD aects 10-15 % of adults (10). Surgical treatment plays an
important role in the management of this disease for which a
wide range of treatment approaches are present. Although the
main goal in the evolution of surgical treatment is to decrease
neurological compression, surgery including stabilization and
fusion of the mobile segment is applied afterwards. In order to
protect the moving segment, total intervertebral discectomy
and subsequent application of disc prosthesis or interbody
cages, and addition of dynamic instrumentation techniques
have been used. Despite the fast development of minimally
invasive percutaneous lumbar instrumentation techniques,
the need for general anesthesia in most of the approaches
and unsatisfactory patient satisfaction have led to a search for
new treatment techniques with less invasive percutaneous
approaches (5).
Considering the pathophysiology of DDD, it can be
hypothesized that increasing the amount of water in the
nucleus could increase disc elasticity and decrease the
complaints. Using implants in minimally invasive spinal
surgery has therefore considered, as they were formerly
used in plastic surgery, orthopedic surgery and gynecologic
Hydrogel is highly compatible with the surrounding tissue. Its
application volume is low, it causes little inammation, and it
can absorb ten times more water than its own volume (4). Many
studies have been performed before spinal application and
the molecule has been developed. Many in vivo and in vitro
studies by spinal applications of improved hydrogel implants
are present, and it is concluded that hydrogel implants aect
DDD prognosis positively, increase the amount of water in
the disc, increase pH, increase lumber ROM angles and are is
safe to insert (1,2,4,5,6,8,10). Subsequent to these studies, the
developed hydrogels have been used in clinical practice and
the presented trademark is Gelstix
is indicated for patients who have adequate disc
height (>3 mm) and black disc feature at MRI, and whose
main complaint is axial discogenic pain when there is no
Figure 1: Sagittal
T2 weighted MRI
imaging of the
patient before
insertion of
annular tear (10). It is inserted into the nucleus pulposus with
the discography technique. After placement, it can absorb
water 10-fold its weight in about 15 minutes (10). Although
little is known about the implant, results of the studies so far
show that the patient benet is favorable (10). (10).
In the evaluation of the patient, it was found that Gelstix was
placed in another clinic four months ago, but there was no
improvement in axial low back pain. Due to severe radicular
pain at follow up, the patient was explored microsurgically
although there was no signicant problem on MRI except
the hiperintense zone on T2-weighted MRI scans. During the
surgery with a classic posterior approach, it was seen that
had fragmented into the epidural space. This might
have happened in two ways:
1: An implant which is placed correctly may come into the
epidural space through a new annular tear. A correctly placed
implant takes a high volume of water in a short time, and can
hardly become fragmented in its former location.
2: An implant that is placed in the bers of the annulus brosus
(false location) may be due to a new or former annular tear by
mobilisation as time passes.
We could not obtain the scopy images of the percutaneous
invervention. Although MRI scans before the insertion of
did not exactly show a black disc on the level of L5-S1,
there was loss of T2 signal at the disc space. Our preoperative
MRI inspection did not show hyperintensity in the disc at the
L5-S1 level that should be seen at the T2 sequence as a proof
of increased hydration (10). Consequently, it is considered that
the implant was incorrectly placed into the annulus bers.
A few complications related to hydrogel usage as dura
adhesive in neurosurgery have been reported (7,9). However,
no complication related to Gelstix
application has been
Turk Neurosurg 2014, Vol: 24, No: 4, 602-605604
Durdag E. et al: Fragmentation of Gelstix
to Epidural Space
reported until now. Our case is therefore important as it
describes the rst complication related to the issue.
Diculty during placement during the application of
minimally invasive hydogel implant in the disc can cause
unfavourable results proceeding to surgery. Hyperintensity of
annulus brosus on T2-weighted MRI scans of patients with
hydrogel-based implants may indicate fragmentation of the
implant. The technique of placement is important in order
not to turn minimally invasive surgery into a complication
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Figure 2: A Pre-
operative sagittal T2
weighted MRI imaging
of the patient.
B Pre-operative axial T2
weighted MRI imaging
of the patient.
C Operative image
from microscope: White
star: neural root, white
arrow: fragmented
D Excised fragment of
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to Epidural Space
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... 511 DiscMaxx HydroGel TM (Replication Medical, Inc., Monmouth Junction, NJ, USA), also known as Gelstix TM , is composed of hydrolyzed polyacrylonitrile that absorbs the surrounding fluid to restore NP hydration and biomechanical properties. 512,513 BioDisc TM , composed of albumin and glutaraldehyde, is injectable through a dual syringe delivery system, with polymerization occurring during the delivery process. 514 NuCore ® injectable nucleus (Spine Wave, Shelton, CT, USA), comprising a sequential block copolymer of silk and elastin components, is first mixed with a crosslinker and immediately injected into the NP through the AF defect, allowing polymerization at the surrounding tissue. ...
... 25, 513 However, without a restraining device, fragments of Gelstix TM hydrogels were found to dislocate and compress the spinal root. 513 Therefore, the safety and efficacy of existing commercial devices should be further assessed with more extensive trials and a larger sample size. ...
... NP materials that cannot withstand hydrostatic pressure within the disc are likely to cause excessive stress on the surrounding AF and endplate, leading to progressive disc degeneration. 513 Furthermore, mechanical restoration is a tremendous challenge for AF reparative materials, as AF suffers from an asymmetric "push-out" force transduced from the NP tissue and an axial force from endplates. Therefore, additional studies should be performed to satisfy the mechanical requirements of AF regeneration. ...
Full-text available
Low back pain is a vital musculoskeletal disease that impairs life quality, leads to disability and imposes heavy economic burden on the society, while it is greatly attributed to intervertebral disc degeneration (IDD). However, the existing treatments, such as medicines, chiropractic adjustments and surgery, cannot achieve ideal disc regeneration. Therefore, advanced bioactive therapies are implemented, including stem cells delivery, bioreagents administration, and implantation of biomaterials etc. Among these researches, few reported unsatisfying regenerative outcomes. However, these advanced therapies have barely achieved successful clinical translation. The main reason for the inconsistency between satisfying preclinical results and poor clinical translation may largely rely on the animal models that cannot actually simulate the human disc degeneration. The inappropriate animal model also leads to difficulties in comparing the efficacies among biomaterials in different reaches. Therefore, animal models that better simulate the clinical charateristics of human IDD should be acknowledged. In addition, in vivo regenerative outcomes should be carefully evaluated to obtain robust results. Nevertheless, many researches neglect certain critical characteristics, such as adhesive properties for biomaterials blocking annulus fibrosus defects and hyperalgesia that is closely related to the clinical manifestations, e.g., low back pain. Herein, in this review, we summarized the animal models established for IDD, and highlighted the proper models and parameters that may result in acknowledged IDD models. Then, we discussed the existing biomaterials for disc regeneration and the characteristics that should be considered for regenerating different parts of discs. Finally, well-established assays and parameters for in vivo disc regeneration are explored.
... It is also easier for a soft material to be extruded out of the disc from the annulus incision or fragment inside the patient body. 18,19 To date, biomaterials for the treatment of degenerated NP are either synthetically manufactured permanent acellular implants 20 or degradable materials which rely on cell growth and proliferation to form neo-NP tissue at the site of degeneration to illicit repair. 21 In all NP replacement strategies, the mechanical properties of biomaterials are of great significance. ...
... 125 However, for this approach, making a cohesive implant is challenging and due to the lack of integrated bulk construct, the fragmentation of thin hydrogel filaments and the subsequent extrusion from the AF incision may be problematic. 19 46 Most importantly, dynamic loading should be induced based on physiologically relevant loading conditions (shown in Table 1); harsh testing conditions may indicate the effectiveness and intactness of the implant in vivo. ...
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Biomaterials for nucleus pulposus (NP) replacement and regeneration have great potential to restore normal biomechanics in degenerated intervertebral discs following nucleotomy. Mechanical characterizations are essential for assessing the efficacy of biomaterial implants for clinical applications. While traditional compression tests are crucial to quantify various modulus values, relaxation behaviors and fatigue resistance, rheological measurements should also be conducted to investigate the viscoelastic properties, injectability, and overall stability upon deformation. To recapitulate the physiological in vivo environment, the use of spinal models is necessary to evaluate the risk of implant extrusion and the restoration of biomechanics under different loading conditions. When designing devices for NP replacement, injectable materials are ideal to fully fill the nucleus cavity and prevent implant migration. In addition to achieving biocompatibility and desirable mechanical characteristics, biomaterial implants should be optimized to avoid implant extrusion or re-herniation post-operatively. This review discusses the most commonly used testing protocols for assessing mechanical properties of biomaterial implants and serves as reference material for enabling researchers to characterize NP implants through a unified approach whereby newly developed biomaterials may be compared and contrasted to existing devices.
... The reason is that although they achieve biomechanical restoration close to but not equal to an intact intervertebral disc, 24,26,36,51−56 extrusion and subsidence are not fully solved yet. 32,33,45,57,58 Annulus functional restoration is paramount to recovering intervertebral disc biomechanics 12 as this keeps intradiscal pressure within normal ranges and minimizes extrusion risk. 12,59−61 Different ways have been attempted. ...
... 55 In addition, some of these materials fracture or break under cycling loading. 45 Some designs have an outside bag that prevents the spillage of implant debris, but the injected core-curing process poses another challenge. 51,53 Implants with an uneven load distribution have a higher subsidence risk, 56 which is minimized in those with a central void cavity. ...
Full-text available
Design: cadaveric spine nucleus replacement study. Objective: determining Bionate 80A nucleus replacement biomechanics in cadaveric spines. Methods: in cold preserved spines, with ligaments and discs intact, and no muscles, L3-L4, L4-L5, and L5-S1 nucleus implantation was done. Differences between customized and overdimensioned implants were compared. Flexion, extension, lateral bending, and torsion were measured in the intact spine, nucleotomy, and nucleus implantation specimens. Increasing load or bending moment was applied four times at 2, 4, 6, and 8 Nm, twice in increasing mode and twice in decreasing mode. Spine motion was recorded using stereophotogrammetry. Expulsion tests: cyclic compression of 50-550 N for 50,000 cycles, increasing the load until there was extreme flexion, implant extrusion, or anatomical structure collapse. Subsidence tests were done by increasing the compression to 6000 N load. Results: nucleotomy increased the disc mobility, which remained unchanged for the adjacent upper level but increased for the lower adjacent one, particularly in lateral bending and torsion. Nucleus implantation, compared to nucleotomy, reduced disc mobility except in flexion-extension and torsion, but intact mobility was no longer recovered, with no effect on upper or lower adjacent segments. The overdimensioned implant, compared to the customized implant, provided equal or sometimes higher mobility. Lamina, facet joint, and annulus removal during nucleotomy caused more damaged than that restored by nucleus implantation. No implant extrusion was observed under compression loads of 925-1068 N as anatomical structures collapsed before. No subsidence or vertebral body fractures were observed under compression loads of 6697.8-6812.3 N. Conclusions: nucleotomized disc and L1-S1 mobility increased moderately after cadaveric spine nucleus implantation compared to the intact status, partly due to operative anatomical damage. Our implant had shallow expulsion and subsidence risks.
... NP replacements also present some challenges. An NPR in the form of hydrogels was reported to have swelling issues, which may trigger gel fragmentation [28] and inflammation [29]. ...
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Various implant treatments, including total disc replacements, have been tried to treat lumbar intervertebral disc (IVD) degeneration, which is claimed to be the main contributor of lower back pain. The treatments, however, come with peripheral issues. This study proposes a novel approach that complies with the anatomical features of IVD, the so-called monolithic total disc replacement (MTDR). As the name suggests, the MTDR is a one-part device that consists of lattice and rigid structures to mimic the nucleus pulposus and annulus fibrosus, respectively. The MTDR can be made of two types of thermoplastic polyurethane (TPU 87A and TPU 95A) and fabricated using a 3D printing approach: fused filament fabrication. The MTDR design involves two configurations—the full lattice (FLC) and anatomy-based (ABC) configurations. The MTDR is evaluated in terms of its physical, mechanical, and cytotoxicity properties. The physical characterization includes the geometrical evaluations, wettability measurements, degradability tests, and swelling tests. The mechanical characterization comprises compressive tests of the materials, an analytical approach using the Voigt model of composite, and a finite element analysis. The cytotoxicity assays include the direct assay using hemocytometry and the indirect assay using a tetrazolium-based colorimetric (MTS) assay. The geometrical evaluation shows that the fabrication results are tolerable, and the two materials have good wettability and low degradation rates. The mechanical characterization shows that the ABC-MTDR has more similar mechanical properties to an IVD than the FLC-MTDR. The cytotoxicity assays prove that the materials are non-cytotoxic, allowing cells to grow on the surfaces of the materials.
... Durdag and colleagues reoperated a woman with a GelStix ® implanted as she was admitted with severe radicular pain. 149 The pain was linked to a fragment of implant that had penetrated through an annual tear and caused compression to the spinal root. The authors speculate that the implant may have been initially wrongly placed in the AF, highlighting the importance of the correct placement of the implant. ...
Full-text available
Musculoskeletal defects are an enormous healthcare burden and source of pain and disability for individuals. With an ageing population, the proportion living with these medical indications will increase. Simultaneously, there is pressure on healthcare providers to source efficient solutions, which are cheaper and less invasive than conventional technology. This has led to an increased research focus on hydrogels as highly biocompatible biomaterials that can be delivered through minimally invasive procedures. This review will discuss how hydrogels can be designed for clinical translation, particularly in the context of the new European Medical Device Regulation (MDR). We will then do a deep dive into the clinically used hydrogel solutions that have been commercially approved or have undergone clinical trials in Europe or the US. We will discuss the therapeutic mechanism and limitations of these products. Due to the vast application areas of hydrogels, this work focuses only on treatments of cartilage, bone, and the nucleus pulposus. Lastly, the main steps towards clinical translation of hydrogels as medical devices are outlined. We suggest a framework for how academics can assist small and medium MedTech enterprises conducting the initial clinical investigation and Post‐Market Clinical Follow‐up (PMCF) required in the MDR. It is evident that the successful translation of hydrogels is governed by acquiring high‐quality pre‐clinical and clinical data confirming the device mechanism of action and safety. This article is protected by copyright. All rights reserved.
... 7 Many nucleus disc replacements have been designed in the past, with only a few reaching the market 8 and even less still in clinical use. The problems are varied and include material degradation, 9 design flaws, extrusion, 10 and subsidence 11 the search for the ideal nucleus replacement material and design continues. 12 Therefore, we decided to create a new nucleus implant based on past issues and failures. ...
Full-text available
Study design: Biomechanical study of a nucleus replacement with a finite element model. Objective: To validate a Bionate 80A ring-shaped nucleus replacement. Methods: The ANSYS lumbar spine model made from lumbar spine X-rays and magnetic resonance images obtained from cadaveric spine specimens were used. All materials were assumed homogeneous, isotropic, and linearly elastic. We studied three options: intact spine, nucleotomy, and nucleus implant. Two loading conditions were evaluated at L3-L4, L4-L5, and L5-S1 discs: a 1000 N axial compression load and this load after the addition of 8 Nm flexion moment in the sagittal plane plus 8 Nm axial rotation torque. Results: Maximum nucleus implant axial compression stresses in the range of 16–34 MPa and tensile stress in the range of 5–16 MPa, below Bionate 80A resistance were obtained. Therefore, there is little risk of permanent implant deformation or severe damage under normal loading conditions. Nucleotomy increased segment mobility, zygapophyseal joint and end plate pressures, and annulus stresses and strains. All these parameters were restored satisfactorily by nucleus replacement but never reached the intact status. In addition, annulus stresses and strains were lower with the nucleus implant than in the intact spine under axial compression and higher under complex loading conditions. Conclusions: Under normal loading conditions, there is a negligible risk of nucleus replacement, permanent deformation or severe damage. Nucleotomy increased segmental mobility, zygapophyseal joint pressures, and annulus stresses and strains. Nucleus replacement restored segmental mobility and zygapophyseal joint pressures close to the intact spine. End plate pressures were similar for the intact and nucleus implant conditions under both loading modes. Manufacturing customized nucleus implants is considered feasible, as satisfactory biomechanical performance is confirmed.
... These hydrogels are mainly derived from non-degradable polyacrylates and polyacrylamides [10,11] and degradable hyaluronic acid, collagen in the extracellular matrix and chitosan [8,12]. However, these implanted materials often failed to regulate the post-injury microenvironment, and tissue degeneration, water loss and inflammatory reaction often appeared in situ [13,14]. Regarding AF, structural repair is a hot spot. ...
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Tissue specificity, a key factor in the decellularized tissue matrix (DTM), has shown bioactive functionalities in tuning cell fate—e.g., the differentiation of mesenchymal stem cells. Notably, cell fate is also determined by the living microenvironment, including material composition and spatial characteristics. Herein, two neighboring tissues within intervertebral discs, the nucleus pulposus (NP) and annulus fibrosus (AF), were carefully processed into DTM hydrogels (abbreviated DNP-G and DAF-G, respectively) to determine the tissue-specific effects on stem cell fate, such as specific components and different culturing methods, as well as in vivo regeneration. Distinct differences in their protein compositions were identified by proteomic analysis. Interestingly, the fate of human bone marrow mesenchymal stem cells (hBMSCs) also responds to both culturing methods and composition. Generally, hBMSCs cultured with DNP-G (3D) differentiated into NP-like cells, while hBMSCs cultured with DAF-G (2D) underwent AF-like differentiation, indicating a close correlation with the native microenvironments of NP and AF cells, respectively. Furthermore, we found that the integrin-mediated RhoA/LATS/YAP1 signaling pathway was activated in DAF-G (2D)-induced AF-specific differentiation. Additionally, the activation of YAP1 determined the tendency of NP- or AF-specific differentiation and played opposite regulatory effects. Finally, DNP-G and DAF-G specifically promoted tissue regeneration in NP degeneration and AF defect rat models, respectively. In conclusion, DNP-G and DAF-G can specifically determine the fate of stem cells through the integrin-mediated RhoA/LATS/YAP1 signaling pathway, and this tissue specificity is both compositional and spatial, supporting the utilization of tissue-specific DTM in advanced treatments of intervertebral disc degeneration.
... A copolymeric hydrogel, with the longest history of clinical use, has served as an alternative to NP. However, similar to previously used in situ hydrated polymers, some complications have already been reported, including gel fragmentation during swelling [73]. Other biomaterials, such as NP implant devices, have been developed from an injectable polymer that physically transitions to a gel or solid form. ...
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Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain (LBP) that results in serious disability and significant economic burden. IVD degeneration alters the disc structure and spine biomechanics, resulting in subsequent structural changes throughout the spine. Currently, treatments of chronic LBP due to IVD degeneration include conservative treatments, such as pain medication and physiotherapy, and surgical treatments, such as removal of herniated disc without or with spinal fusion. However, none of these treatments can completely restore a degenerated disc and its function. Thus, although the exact pathogenesis of disc degeneration remains unclear, there are studies examining the effectiveness of biological approaches, such as growth factor injection, gene therapy, and cell transplantation, in promoting IVD regeneration. Furthermore, tissue engineering using a combination of cell transplantation and biomaterials has emerged as a promising new approach for repair or restoration of degenerated discs. The main purpose of this review was to provide an overview of the current status of tissue engineering applications for IVD regenerative therapy by performing literature searches using PubMed. Significant advances in tissue engineering have opened the door to a new generation of regenerative therapies for the treatment of chronic discogenic LBP.
... While some pain reduction has been seen, the outcomes are mechanical in nature and lack any biologically active component that could cause regeneration (33,34). Additionally, complications are prevalent with biomaterials, including biomaterial leaking out of the disc and causing additional pain, and excess stiffness causing endplate fracture (35,36). As a result, neither anti-inflammatory proteins nor biomaterials present an ideal approach to treating DD. ...
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Low back pain (LBP) is a serious medical condition that affects a large percentage of the population worldwide. One cause of LBP is disc degeneration (DD), which is characterized by progressive breakdown of the disc and an inflamed disc environment. Current treatment options for patients with symptomatic DD are limited and are often unsuccessful, so many patients turn to prescription opioids for pain management in a time when opioid usage, addiction, and drug-related deaths are at an all-time high. In this paper, we discuss the etiology of lumbar DD and currently available treatments, as well as the potential for cell therapy to offer a biologic, non-opioid alternative to patients suffering from the condition. Finally, we present an overview of an investigational cell therapy called IDCT (Injectable Discogenic Cell Therapy), which is currently under evaluation in multiple double-blind clinical trials overseen by major regulatory agencies. The active ingredient in IDCT is a novel allogeneic cell population known as Discogenic Cells. These cells, which are derived from intervertebral disc tissue, have been shown to possess both regenerative and immunomodulatory properties. Cell therapies have unique properties that may ultimately lead to decreased pain and improved function, as well as curb the numbers of patients pursuing opioids. Their efficacy is best assessed in rigorous double-blinded and placebo-controlled clinical studies.
... Gelstix TM is a hydrogel implant indicated in discogenic back pain when there is no annular tear. Durdag et al. reported epidural fragmentation of hydrogel implant causing sciatica which required surgery 9) . ...
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A 40-year-old male presented with right sided sciatica due to L3-L4 disc prolapse. Patient was treated with transforaminal endoscopic discectomy L3-L4 and platelet fibrin plug application under local anaesthesia. Patient had good relief from pain after the procedure. At one month after the surgery, patient developed recurrent sciatica. Magnetic resonance imaging revealed recurrent compression at the operated level. Patient was treated with repeat transforaminal endoscopic surgery. Transforaminal endoscopy revealed epidural migration of the platelet fibrin plug and was removed. Patients had immediate relief from radicular pain with no further recurrence. Histopathology report confirmed that it was migrated platelet fibrin plug. As the platelet fibrin plug does not have any fixation in the disc, it carries a significant risk of epidural migration and recurrent sciatica.
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Hydrogels are water-insoluble hydrophilic polymers used in a wide range of medical products such as, drug delivery, tissue replacement, heart surgery, gynaecology, ophthalmology, plastic surgery and orthopaedic surgery. These polymers exhibit low toxicity, reduced tissue adherence, and are highly biocompatible. A class of hydrogels, hydrolysed polyacrylonitriles, possess unique shape memory properties, which, when combined with biodurability, mechanical strength and viscoelasticity make them ideal for treating certain degenerative conditions of the spine. Animal and other in vitro studies have shown that the hydrogel is biocompatible and well tolerated by host tissues. This article focuses on two specific indications in spine surgery that demonstrate the potential of hydrogel-based technology to provide significant treatment advantages.
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Regenerative repair is a promising new approach in treating damaged intervertebral discs. An experimental scheme was established for autologous and/or allogenic repair after massive disc injury. Disc healing was promoted in 11 animals by injecting in vitro expanded autologous/homologous disc cells 2 weeks after stab injury of lumbar discs L1-2. The following control discs were used in our sheep injury model: L2-3, vehicle only; L3-4, injury only; L4-5, undamaged; and lumbar discs from four non-experimental animals. Disc cells were suspended in a biologically supportive albumin/hyaluronan two-component hydrogel solution that polymerizes when inserted in order to anchor cells at the injection site. The parameters studied were MRI, DNA, glycosaminoglycan, collagen content, histology, immunohistology for collagens type I, II and aggrecan, and mRNA expression of GAPDH, β-actin, collagen type I, II, X, aggrecan, lubricin, and IL-1β. All parameters demonstrated almost complete healing of the injured discs after 6 months, when compared with data from both the endogenous non-injured controls as well as from the healthy animals. Sheep experience spontaneous recovery from disc injury. The process of endogenous repair can be enhanced by means of hydrogel-supported cells.
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Cell-based approaches towards restoration of prolapsed or degenerated intervertebral discs are hampered by a lack of measures for safe administration and placement of cell suspensions within a treated disc. In order to overcome these risks, a serum albumin-based hydrogel has been developed that polymerizes after injection and anchors the administered cell suspension within the tissue. A hydrogel composed of chemically activated albumin crosslinked by polyethylene glycol spacers was produced. The visco-elastic gel properties were determined by rheological measurement. Human intervertebral disc cells were cultured in vitro and in vivo in the hydrogel and their phenotype was tested by reverse-transcriptase polymerase chain reaction. Matrix production and deposition was monitored by immuno-histology and by biochemical analysis of collagen and glycosaminoglycan deposition. Species specific in situ hybridization was performed to discriminate between cells of human and murine origin in xenotransplants. The reproducibility of the gel formation process could be demonstrated. The visco-elastic properties were not influenced by storage of gel components. In vitro and in vivo (subcutaneous implants in mice) evidence is presented for cellular differentiation and matrix deposition within the hydrogel for human intervertebral disc cells even for donor cells that have been expanded in primary monolayer culture, stored in liquid nitrogen and re-activated in secondary monolayer culture. Upon injection into the animals, gels formed spheres that lasted for the duration of the experiments (14 days). The expression of cartilage- and disc-specific mRNAs was maintained in hydrogels in vitro and in vivo, demonstrating the maintenance of a stable specific cellular phenotype, compared to monolayer cells. Significantly higher levels of hyaluronan synthase isozymes-2 and -3 mRNA suggest cell functionalities towards those needed for the support of the regeneration of the intervertebral disc. Moreover, mouse implanted hydrogels accumulated 5 times more glycosaminoglycans and 50 times more collagen than the in vitro cultured gels, the latter instead releasing equivalent quantities of glycosaminoglycans and collagen into the culture medium. Matrix deposition could be specified by immunohistology for collagen types I and II, and aggrecan and was found only in areas where predominantly cells of human origin were detected by species specific in situ hybridization. The data demonstrate that the hydrogels form stable implants capable to contain a specifically functional cell population within a physiological environment.
A hydrogel nucleus pulposus prosthesis (NPP) was designed to swell in situ, have intrinsic radiopacity, and restore intervertebral disc height and biomechanical functionality. These features were examined using an ex vivo canine lumbar model. Nine NPPs were implanted in five spines and their visibility was assessed on radiography, computed tomography (CT), and magnetic resonance imaging (MRI). The NPPs were visible on all imaging modalities and 8/9 NPPs stayed intact and in situ. Six other NPPs were tested biomechanically in six canine lumbar spines. Removal of the nucleus pulposus (nuclectomy) caused significant changes in biomechanical parameters. After implantation and swelling of the NPP, values were not significantly different from the native state for range of motion (ROM) of flexion-extension (FE) and lateral bending (LB), the neutral zone (NZ) of all motion directions, and the NZ stiffness (NZS) of FE. Biomechanical restoration by the NPP compared with the nuclectomized state was significant for the ROM of FE and axial rotation, the NZ of FE and LB, and the NZS of FE and LB. Disc height was significantly restored and 6/6 NPPs stayed intact and in situ. In conclusion, the NPPs swell in situ, have intrinsic radiopacity and restored disc height and aforementioned biomechanical properties. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012.
Investigation of injectable nucleus pulposus (NP) implant. To assess the ability of a recently developed injectable hydrogel implant to restore nondegenerative disc mechanics through support of NP functional mechanics. Although surgical intervention for low back pain is effective for some patients, treated discs undergo altered biomechanics and adjacent levels are at increased risk for accelerated degeneration. One potential treatment as an alternative to surgery for degenerated disc includes the percutaneous delivery of agents to support NP functional mechanics. The implants are delivered in a minimally invasive fashion, potentially on an outpatient basis, and do not preclude later surgical options. One of the challenges in designing such implants includes the need to match key NP mechanical behavior and mimic the role of native nondegenerate NP in spinal motion. The oxidized hyaluronic acid gelatin implant material was prepared. In vitro mechanical testing was performed in mature ovine bone-disc-bone units in 3 stages: intact, discectomy, and implantation versus sham. Tested samples were cut axially for qualitative structural observations. Discectomy increased axial range of motion (ROM) significantly compared with intact. Hydrogel implantation reduced ROM 17% (P < 0.05) compared with discectomy and returned ROM to intact levels (ROM intact 0.71 mm, discectomy 0.87 mm, postimplantation 0.72 mm). Although ROM for the hydrogel implant group was statistically unchanged compared with the intact disc, ROM for sham discs, which received a discectomy and no implant, was significantly increased compared with intact. The compression and tension stiffness were decreased with discectomy and remained unchanged for both implant and sham groups as expected because the annulus fibrosus was not repaired. Gross morphology images confirmed no ejection of NP implant. An injectable implant that mimics nondegenerate NP has the potential to return motion segment ROM to normal subsequent to injury.
An injectable hydrogel, acting as a reservoir for cell delivery and mimicking the native environment, offers promise for nucleus pulposus (NP) repair and regeneration. Herein, the potential of a stabilised type II collagen hydrogel using poly(ethylene glycol) ether tetrasuccinimidyl glutarate (4S-StarPEG) cross-linker, enriched with hyaluronic acid (HA) was investigated. The optimally stabilised type II collagen hydrogel was determined by assessing free amine groups, resistance to enzymatic degradation, gel point. The potential toxicity of the cross-linker was initially assessed against adipose-derived stem cells (ADSCs). After addition of HA (molar ratio type II collagen:HA 9:0, 9:1, 9:4.5, 9:9) within the hydrogel, the behaviour of the encapsulated NP cells was evaluated using cell proliferation assay, gene expression analysis, cell distribution and cell morphology. A significant decrease (p < 0.05) in the free amine groups of collagen was observed, confirming successful cross-linking. Gelation was independent of the concentration of 4S-StarPEG (8 min at 37 °C). The 1 mm cross-linked hydrogel yielded the most stable after enzymatic degradation (p < 0.05). No toxicity of the 4S-StarPEG was noted for the ADSCs. NP cell viability was high regardless of the concentration of HA (>80%). A cell proliferation was not seen after 14 days in its presence. At a gene expression level, HA did not influence NP cells phenotype after seven days in culture. After seven days in culture, the type I collagen mRNA expression was maintained (p > 0.05). The optimally stabilised and functionalised type II collagen/HA hydrogel system developed in this study shows promise as an injectable reservoir system for intervertebral disc regeneration.
The degeneration of intervertebral disc (IVD) is a major cause of low back pain. However, there is no satisfactory preventive treatment for degenerative disc disease (DDD). In this study, we examined the effects of a novel cross-linked hyaluronate hydrogel and cross-linked chondroitin sulfate (CS) hydrogel on a rabbit model of IVD injury. We injected 300 microl of phosphate buffer saline, 1% sodium hyaluronate, cross-linked hyaluronate hydrogel, or cross-linked CS hydrogel into the injured IVDs. One, three or six months after treatment, the whole spinal columns were dissected and magnetic resonance (MR) images of the IVDs were examined. It was noted that the IVD, which was injected with cross-linked hyaluronate hydrogel or cross-linked CS hydrogel mostly retained the normal signal intensity of the MR images. These IVDs exhibited a higher degree of staining with safranin-O than the control discs or 1% sodium hyaluronate-injected discs, suggesting that the intradiscal application of cross-linked hyaluronate hydrogel or cross-linked CS hydrogel probably inhibits the degenerative cascade of the DDD. The intradiscal administration of these drugs is safe, easy and costs less. In the near future, these intradiscal injections may become the standard therapy for the treatment of DDD instead of the spine surgeries.
A retrospective case report. To raise the issue of DuraSeal for dural tear repair; to raise the issue of the potential for fatal consequences, if not considered to be an issue around and after surgery; and to illustrate this with a case. Cerebrospinal fluid leak is a potential complication of spinal, and posterior fossa surgery. Leakage may be caused by inadvertent dural tears during decompressive laminectomy or extradural spinal approaches, for spinal surgery. We present the case of a complication as a result of repair for dural tear with hydrogel. History, focused neurologic examination with pre- and postoperative magnetic resonance scan images. C5-C6 anterior cervical discectomy, and fusion with a standard commercial PEEK space cage. Intraoperatively there was a small cerebrospinal leak when excising the posterior longitudinal ligament. Surgicel and DuraSeal were used to seal this. The patient developed a quadriparesis after surgery which was a result of expansion of the hydrogel seen on MRI and at re-exploration. Hydrogel is now described for the second time to cause potentially fatal expansion.
The authors present a case of cauda equina compression after laminotomy and discectomy where incidental durotomy was managed with the application of hydrogel sealant. The patient reported return of radicular symptoms on the first postoperative day, and deterioration to early cauda equina syndrome after bending on the sixth day. To demonstrate that in addition to its recognized volume expansion properties, that the product has the ability to migrate and produce symptoms remote from where it was inserted. The physical properties of DuraSeal (Confluent Surgical, Waltham, MA), a hydrogel dural sealant, make it an effective adjunct to dural closure. Its volume expansion has been associated with neural compression after posterior fossa decompression. We have found no reported migration of this product. Sequential postoperative imaging shows swelling and migration of the hydrogel into spinal canal with resultant compression. Exploration on postoperative day 10 revealed sealant causing cauda equina compression proximal to the site of the durotomy. The authors recommend that in addition to caution regarding its potential mass effect, that cognizance be taken of the product's potential to migrate and result in symptoms at a distant site.