The Science. The Research.
Treatment of annular disc tears and “leaky disc syndrome” with fibrin sealant
Available online 24 November 2016, Version of Record 14 December 2016.
Abstract
The surfaces of annulus fibrosus tears are known harbingers of inflammatory constituents within intervertebral discs, stimulating sensitized nocioceptors within those tears. Other current treatment options of internal disc disruption neglect to specifically address the surface of these tears. Therefore, this investigation answers the question: does nonautologous fibrin sealant applied to the surface of annulus fibrosus tears mechanically glue and seal annular tears? Regarding this query, results suggest nonautologous concentrated fibrin successfully seals annulus fibrosus tears with a “suture-like mechanical sealant,” serving as a safe option for treating symptomatic or nonsymptomatic intervertebral disc tears. Sealing tears prevents pain-generating chemicals of the nucleus pulposus from leaking through annular tears. More specifically, fibrin sealant minimizes or eliminates extravasation of nucleus pulposus through tears and voids within the annulus fibrosus. Moreover, an investigation subjecting discs to an “internal pressure challenge” objectively affirms fibrin׳s ability to seal torn and degenerated discs against a pressure challenge. (1 psi = 6.89476 kPs (disc mean pressure pretreatment = 75.84 kPs; post-treatment = 179.3 kPs: (n = 347, P < 0.001). Therefore, sealing annular tears serves to minimize extravasation of nucleus pulposus through annular tears, thus potentially treating symptoms caused by internal disc disruption, “Leaky Disc Syndrome,” and chemical radiculopathy. Additionally, sealing annular tears potentially allows adjunctive regenerative biologics such as mesenchymal precursor cells, platelet rich plasma, and growth factors to remain within discs, thus, potentially optimizing their efficacy. A prior in vivo investigation demonstrated the vast majority of mesenchymal stem cells leaked from animal intravertebral discs, and another demonstrated radiolabeled mesenchymal stem cells leaked from degenerated discs and were subsequently found within new exuberant osteophytes adjacent to the degenerated disc. Intra-annular nonautologous concentrated fibrin shares a benefit of other intradiscal biologics in that fibrin does not cause aberrant detrimental mechanical forces on adjacent discs, compared with surgical fusion and disc arthrodesis, which both cause aberrant, potentially damaging mechanical forces on adjacent segments. The mean number of morphologically abnormal lumbar intervertebral discs in this population with chronic low back pain was 3.21 discs.
Author(s):
Pooya Torkian, ORCID iD: 0000-0001-6147-8145,1
Keivan Daneshvar, ORCID iD: 0000-0002-0345-0379,2
Ebrahim Taherian, ORCID iD: 0000-0003-4942-4528,3
Yasaman Rezaeifar, ORCID iD: 0000-0001-6535-5062,4
Shahram Akhlaghpoor3
Abstract:
Fibrin sealant as a promising agent for providing scaffold and efficient hemostasis is widely accepted in several specialties. However, the outcome of Fibrin sealants in lumbar annuloplasty after endoscopic discectomy has not been evaluated in patients with disc herniation. The goal of this study was to evaluate the efficacy, response, and probability of future recurrence rates in herniated nucleus pulposus (HNP) with the use of fibrin sealant in conjunction with endoscopic disc surgery. A total of 35 patients (28 men, 7women) were evaluated, including 18 patients who underwent endoscopic discectomy alone and 17 patients that received fibrin sealant at the site of annulus tear and endoscopic discectomy. All patients were followed through both clinical and imaging methods for an average of 10.5 months. Primary outcome measure was defined as lumbar decompression approved by imaging and symptom alleviation after endoscopic spinal discectomy with Visual Analogue Scale (VAS) score ≤ 4 (cut-off point). Median size of annular tearing was significantly lower in the endoscopic discectomy group (median, 3) (minimum, 2; maximum, 5); however, the corresponding factor in the endoscopic discectomy plus fibrin sealant group was significantly larger (median, 6) (minimum, 5; maximum, 10), with P <0.001. Only one patient in the endoscopic discectomy group had an HNP recurrence during follow-up compared to two patients in the endoscopic discectomy plus fibrin sealant group. Due to the temporary effects of fibrin sealant in preventing disc herniation and the observed recurrence rate in both the case and control groups, the results of this study suggest a role of fibrin sealants combined with endoscopic discectomy to prevent early HNP recurrence rate.
Keywords:
Fibrin sealant, endoscopic discectomy, disc herniation
Spine (Phila Pa 1976) . 2011 Aug 15;36(18):E1201-9. doi: 10.1097/BRS.0b013e31820566b2.
- PMID: 21325992
- DOI: 10.1097/BRS.0b013e31820566b2
Abstract
Study design: Surgically denucleated porcine intervertebral discs (IVD) were injected with BIOSTAT BIOLOGX Fibrin Sealant (FS), and the in vivo effects were assessed over time by histological, biochemical, and mechanical criteria.
Objective: The objectives were to test whether the intradiscal injection of FS stimulates disc healing.
Summary of background data: Disc avascularity prevents the deposition of a provisional fibrin scaffold that typically facilitates soft tissue repair. Poor disc wound healing leads to disc damage accumulation and chronic inflammation characterized by overproduction of proinflammatory cytokines and proteolytic enzymes.
Methods: Four lumbar IVDs from each of 31 Yucatan minipigs were randomized to untreated controls; degenerative injury (nucleotomy); and nucleotomy plus FS injection. Animals were killed at 1, 2, 3, 6, and 12 weeks postsurgery. IVDs were harvested to quantify (1) architecture using morphological and histological grading; (2) proteoglycan composition using DMMB assay; (3) cytokine content using ELISA; and (4) mechanical properties using quantitative pressure/volume testing.
Results: There was progressive invasion of annular tissue into the nucleus of nucleotomy discs and concomitant reduction in proteoglycan content. By contrast, FS supplementation inhibited nuclear fibrosis and facilitated proteoglycan content recovery over time. FS discs synthesized significantly less TNF-α than degenerate discs (66% vs. 226%, P < 0.05) and had upregulation of IL-4 (310% vs. 166%) and TGF-β (400% vs. 117%) at 2 to 3 weeks posttreatment. At the third week postsurgery, the denucleated discs were less stiff than controls (pressure modulus 779.9 psi vs. 2754.8 psi; P < 0.05) and failed at lower pressures (250.5 psi vs. 492.5 psi; P < 0.05). The stiffness and leakage pressure of the FS-treated discs recovered to control values after 6 and 12 weeks, respectively.
Conclusion: FS facilitated structural, compositional, and mechanical repair of the surgically damaged IVD. These FS-derived benefits are likely due to its conductive scaffold properties and metabolically active constituents such as thrombin, factor XIII, and aprotinin acetate.
BACKGROUND CONTEXT: Pathologic disc degeneration includes ineffective healing of tissue damage that accumulates over time. Regions of inflammation, neoinnervation, and nociceptor sensitization can lead to chronic discogenic pain. An important component of normal wound healing occurs when fibrin interacts with matrix and cellular structures. The biostimulatory effects of fibrin include fibroblast recruitment, matrix synthesis, and granulation tissue formation. The Biostat Disc Augmentation System has been developed as a fibrin-based treatment for discogenic pain.
Affiliation:1
1 1 Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Galeazzi Orthopaedic Institute , Milan, Italy . PMID: 24961887 DOI: 10.1089/ten.TEB.2014.0158
Abstract
1). Affiliations PMID: 25236589 DOI: 10.1089/ten.TEA.2014.0279
Abstract The intervertebral disc (IVD) presents a limited self-repair ability and cell-based therapies have been suggested to prevent or treat IVD lesions. Fibrin-based scaffolds as cell carriers are promising candidates in IVD tissue engineering, thanks to their ability to be easily delivered into the defect and to adapt to the lesion shape, to support/retain the injected cells into the implantation site and to favor the production of a suitable extracellular matrix (ECM). We evaluated the in vitro and in vivo behavior of human nucleus pulposus (NP) and annulus fibrosus (AF) cells in a clinical-grade collagen-enriched fibrin that has never been tested before for orthopedic applications, comparing it with clinical-grade fibrin. The survival of IVD cells seeded within fibrin or collagen-enriched fibrin and the ECM synthesis were evaluated by biochemical, immunohistochemical, and transcriptional analyses, prior and after subcutaneous implantation of the gels in nude mice. After 28 days of implantation, NP and AF cells were still detectable within explants, produced tissue-specific ECM, and showed a higher content of glycosaminoglycans (GAGs) and type I and II collagen compared to gels before implantation. Both the fibrin gels, enriched or not with collagen, seemed to be suitable for the culture of AF cells, being able to support the homogeneous synthesis of type I collagen, characteristic of the native fibrocartilaginous AF tissue. Differently, fibrin alone was a more suitable matrix for NP culture, supporting the homogeneous deposition of GAGs and type II collagen. In conclusion, our results suggest to combine AF cells with fibrin, enriched or not with collagen, and NP cells with fibrin alone to maintain the typical features of these cell populations, indicating these clinical-grade materials as viable options in cell-based treatments for IVD lesions. Link to full text
Abstract
Previously, we have proven that fibrin and poly(lactic-co-glycolic acid) (PLGA) scaffolds facilitate cell proliferation, matrix production and early chondrogenesis of rabbit articular chondrocytes in in vitro and in vivo experiments. In this study, we evaluated the potential of fibrin/PLGA scaffold for intervertebral disc (IVD) tissue engineering using annulus fibrosus (AF) and nucleus pulposus (NP) cells in relation to potential clinical application. PLGA scaffolds were soaked in cells-fibrin suspension and polymerized by dropping thrombin-sodium chloride (CaCl(2)) solution. A PLGA-cell complex without fibrin was used as control. Higher cellular proliferation activity was observed in fibrin/PLGA-seeded AF and NP cells at each time point of 3, 7, 14 and 7 days using the MTT assay. After 3 weeks in vitro incubation, fibrin/PLGA exhibited a firmer gross morphology than PLGA groups. A significant cartilaginous tissue formation was observed in fibrin/PLGA, as proven by the development of cells cluster of various sizes and three-dimensional (3D) cartilaginous histoarchitecture and the presence of proteoglycan-rich matrix and glycosaminoglycan (GAG). The sGAG production measured by 1,9-dimethylmethylene blue (DMMB) assay revealed greater sGAG production in fibrin/PLGA than PLGA group. Immunohistochemical analyses showed expressions of collagen type II, aggrecan core protein and collagen type I genes throughout in vitro culture in both fibrin/PLGA and PLGA. In conclusion, fibrin promotes cell proliferation, stable in vitro tissue morphology, superior cartilaginous tissue formation and sGAG production of AF and NP cells cultured in PLGA scaffold. The 3D porous PLGA scaffold-cell complexes using fibrin can provide a vehicle for delivery of cells to regenerate tissue-engineered IVD tissue.
- PMID: 18727862
- DOI: 10.1163/156856208785540163
Abstract
Previously, we have proven that fibrin and poly(lactic-co-glycolic acid) (PLGA) scaffolds facilitate cell proliferation, matrix production and early chondrogenesis of rabbit articular chondrocytes in in vitro and in vivo experiments. In this study, we evaluated the potential of fibrin/PLGA scaffold for intervertebral disc (IVD) tissue engineering using annulus fibrosus (AF) and nucleus pulposus (NP) cells in relation to potential clinical application. PLGA scaffolds were soaked in cells-fibrin suspension and polymerized by dropping thrombin-sodium chloride (CaCl(2)) solution. A PLGA-cell complex without fibrin was used as control. Higher cellular proliferation activity was observed in fibrin/PLGA-seeded AF and NP cells at each time point of 3, 7, 14 and 7 days using the MTT assay. After 3 weeks in vitro incubation, fibrin/PLGA exhibited a firmer gross morphology than PLGA groups. A significant cartilaginous tissue formation was observed in fibrin/PLGA, as proven by the development of cells cluster of various sizes and three-dimensional (3D) cartilaginous histoarchitecture and the presence of proteoglycan-rich matrix and glycosaminoglycan (GAG). The sGAG production measured by 1,9-dimethylmethylene blue (DMMB) assay revealed greater sGAG production in fibrin/PLGA than PLGA group. Immunohistochemical analyses showed expressions of collagen type II, aggrecan core protein and collagen type I genes throughout in vitro culture in both fibrin/PLGA and PLGA. In conclusion, fibrin promotes cell proliferation, stable in vitro tissue morphology, superior cartilaginous tissue formation and sGAG production of AF and NP cells cultured in PLGA scaffold. The 3D porous PLGA scaffold-cell complexes using fibrin can provide a vehicle for delivery of cells to regenerate tissue-engineered IVD tissue.
Affiliations
1Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, 2 Dublin, Ireland. [email protected].
2School of Engineering, Trinity College Dublin, 2 Dublin, Ireland. [email protected].
3Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, 2 Dublin, Ireland. [email protected].
4School of Engineering, Trinity College Dublin, 2 Dublin, Ireland. [email protected].
5Advanced Materials and Bioengineering Research (AMBER) Centre, Royal College of Surgeons in Ireland & Trinity College Dublin, 2 Dublin, Ireland. [email protected].
- PMID: 29996555
- PMCID: PMC6164980
- DOI: 10.3390/jfb9030043
Abstract
Hydrogels, such as fibrin, offer a promising delivery vehicle to introduce cells into the intervertebral disc (IVD) to regenerate damaged disc tissue as a potential treatment for low back pain. However, fibrin lacks key extracellular matrix (ECM) components, such as collagen (Col) and hyaluronan (HA), normally found in native nucleus pulposus (NP) tissue. The overall aim of this work was to create a fibrin-based hydrogel, by incorporating Col and HA into the matrix to enhance NP-like matrix accumulation using articular chondrocytes (CC). Firstly, we assessed the effect of fibrin concentrations on hydrogel stability, and the viability and proliferation kinetics of articular chondrocytes. Secondly, we investigated the effect of incorporating Col and HA to enhance NP-like matrix accumulation, and finally, examined the influence of various HA concentrations. Results showed that increasing fibrin concentration enhanced cell viability and proliferation. Interestingly, incorporation of HA promoted sGAG accumulation and tended to suppress collagen formation at higher concentrations. Taken together, these results suggest that incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels, which may help advance the clinical potential of commercial cell and biomaterial ventures in the treatment of IVD regeneration.
