Physician Research Patents
Studies have demonstrated the clinical efficacy of the DISCSEEL Procedure in treating disc-related pain.
Authors: Way Yin, MD, Kevin Pauza, MD, Wayne J. Olan, MD, Jeff F. Doerzbacher, MS, and Kevin J. Thorne, PhD
BACKGROUND:
Chronic low back pain is the most common cause of disability worldwide, and to date, no surgical or non-surgical treatment has been shown to reliably provide relief in treating chronic low back pain. Lumbar discs are the most common cause of chronic low back pain, and so this investigation evaluates the safety and efficacy of using non-autologous fibrin, introduced intra-annularly, to treat annular defects causing chronic low back pain. Annulargramā¢Ā is a dynamic test, identifying annular defects and contrast flow patterns within the 22-25 annular layers.Ā Annulargramā¢Ā possess greater sensitivity than does MRI in identifying annular defects, and this dynamic test is somewhat analogous to coronary arteriograms, another dynamic test initially fraught with skepticism before itās widespread acceptance which changed the paradigm evaluating CAD. Favorable results of ongoing investigations suggest thatĀ Annulargramā¢Ā will be a mainstay in treating spine pathology. Previous publishedĀ in vivoĀ investigations demonstrate fibrinās ability to mechanically repair annular defects and stimulate new disc growth, returning all disc biochemical and mechanical properties to normal. This investigation evaluates the amalgam of refinements meant to improve clinical outcome.
PURPOSE:
To evaluate the safety and efficacy of intra-annular fibrin to treat chronic low back pain. Compared to many prior investigations, this investigation evaluates the amalgam of diagnostic and therapeutic refinements meant to improve patient outcomes, including: (1) DiagnosticĀ Annulargramā¢Ā used to identify annular defects; (2) Targeting fibrin to thoseĀ Annulus Fibrosus defects; and (3) Treating each disc in the region of symptoms. of Subjects were treated by the Principle Investigator, and subjects prospectively reported their outcome measures in the Non-surgical Orthobiologics Registry (ROR). Outcome tools measured; pain, physical function, mental health, quality of life, satisfaction, and adverse events, to evaluate the safety and efficacy of intra-annular non-autologous fibrin in treating patients with moderate to severe chronic low back pain.
STUDY DESIGN:
Prospectively reported outcome measures analyzed retrospectively in the ROR.
PATIENT SAMPLE:
Subjects suffering from low back pain, with or without leg pain, for greater than six months duration, who failed prior treatments, including;Ā intra-discal stem cell or precursor cell injections (BMAC), as well as intra-discal PRP,Ā zygapophyseal joint (facet joint) āstem cell or PRP Ā injections,ā physical therapy, fluoroscopically-guided transforaminal or interlaminar epidural injections of corticosteroid, radiofrequency neurotomy, or medial branch blocks to rule out posterior element pain. Several subjects failed to experience relief following surgical discectomy and fusion.
OUTCOME MEASURES:Ā
VAS low back; VAS leg; Numeric Rating Scale (NRS); Bodily Pain; Estimated Utility Score; PROMIS Global Mental Health; Global Physical Health; NASS Patient Satisfaction Index Score; Oswestry Disability Index (ODI); and EuroQuol.
METHODS:
320Ā Subjects with chronic low back pain (LBP) who failed to experience relief following prior spine treatments underwent a screening lumbar MRI and x-ray. Patients without severe vertebral canal stenosis or spinal instability, as determined by lumbar MRI and lateral X-ray, respectively, were enrolled in this investigation. All subjects reported their pre-treatment outcome measures in the ROR, and then underwent diagnostic Annulogramsā¢, with subsequent intra-annular injection of non-autologous fibrin to treat annular defects of all morphologically abnormal intervertebral discs in the region of symptomology. Subjects reported their pre- and post-treatment outcome measures beginning in 2017 to present, assessing; pain, physical function, mental health, quality of life, and patient satisfaction.
RESULTS:
Statistically significant improvement was realized in every outcome tool comparing baseline to; 3-months, 6-months, and 1-year post-treatment. No subject was lost to follow-up or withdrawn, and no subject experienced an adverse event. The results of the longitudinal analysis demonstrated statistically significant improvement in all outcomes measured. Ā Table ______ [js1] reportsĀ the findings of the multiple pairwise comparisons between each time point. The values in each square of the matrix are the Bonferroni-adjusted p-values for each pairwise comparison.
CONCLUSIONS:Ā
Patients with chronic low back pain underwent diagnosticĀ Annulargramā¢Ā to identify disc annular defects, and those defects were repaired using intra-annular injection of non-autologous fibrin. Subjects prospectively reported statistically significant improvement of all outcomes at; 3, 6, and 12 months post-treatment, with no adverse events.
Available online 24 November 2016, Version of Record 14 December 2016.
The surfaces ofĀ annulus fibrosusĀ tears are known harbingers of inflammatory constituents withinĀ intervertebral discs, stimulating sensitized nocioceptors within those tears. Other currentĀ treatmentĀ options of internal disc disruption neglect to specifically address the surface of these tears.
Therefore, this investigation answers the question: does nonautologousĀ fibrin sealantĀ applied to the surface ofĀ annulus fibrosusĀ tears mechanically glue and seal annular tears?
Regarding this query, results suggest nonautologous concentrated fibrin successfully seals annulus fibrosus tears with a āsuture-like mechanical sealant,ā serving as a safe option for treating symptomatic or nonsymptomatic intervertebral disc tears. Sealing tears prevents pain-generating chemicals of theĀ nucleus pulposusĀ from leaking through annular tears. More specifically,Ā fibrin sealantĀ minimizes or eliminates extravasation ofĀ nucleus pulposusĀ through tears and voids within the annulus fibrosus. Moreover, an investigation subjecting discs to an āinternal pressure challengeā objectively affirms fibrin׳s ability to seal torn and degenerated discs against a pressure challenge. (1Ā psi = 6.89476Ā kPs (disc mean pressure pretreatment = 75.84Ā kPs; post-treatment = 179.3Ā kPs: (nĀ = 347,Ā PĀ < 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, āLeaky Disc Syndrome,ā and chemicalĀ 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 ofĀ mesenchymal stem cellsĀ leaked from animal intravertebral discs, and another demonstrated radiolabeledĀ mesenchymal stem cellsĀ 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 discĀ arthrodesis, which both cause aberrant, potentially damaging mechanical forces on adjacent segments. The mean number of morphologically abnormal lumbarĀ intervertebral discsĀ in this population with chronic low back pain was 3.21 discs.
PMID:Ā 32782757
Author(s):
Pooya Torkian,Ā ORCID iD: 0000-0001-6147-8145,1
Keivan Daneshvar,Ā ORCID iD: 0000-0002-0345-0379,2
Ebrahim Taherian,Ā ORCID iD: 0000-0003-4942-4528,3
Yasaman Rezaeifar,Ā 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 ā¤ 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), withĀ PĀ <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.
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.
Ā
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-Ī± than degenerate discs (66% vs. 226%, P < 0.05) and had upregulation of IL-4 (310% vs. 166%) and TGF-Ī² (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:Ā 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.
Alessandra Colombini1, Cristina Ceriani, Giuseppe Banfi, Marco Brayda-Bruno, Matteo Moretti
Affiliation:1
1āØ1 Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Galeazzi Orthopaedic Institute , Milan, Italy .
PMID:Ā 24961887Ā DOI:Ā 10.1089/ten.TEB.2014.0158
Fibrin is clinically employed as a versatile, safe, and clinically applicable sealant and cell carrier. It has been able to support disc cell survival, favor extracellular matrix production, and enhance the efficiency of cell transfer in the intervertebral disc (IVD). The aim of this review was to evaluate how fibrin has been used in vitro, in vivo, and in clinical trials for IVD tissue engineering. Within the in vitro studies, disc cells were cultured in fibrin alone or combined with other materials and a difference in the behavior of nucleus pulposus (NP) and annulus fibrosus (AF) cells was sometimes reported, but in general, the formation of fibrocartilaginous matrix was observed. Moreover, data concerning the fibrin long-term stability and its anti-inflammatory properties were found. Disc cells of human origin were never employed in combination with fibrin in vivo or in clinical trials. In vivo, disc degeneration models used to test the fibrin properties essentially involved NP injuries. The addition of cells, in particular if terminally differentiated, to the injected fibrin seemed to promote a more physiological matrix in comparison with fibrin alone. Important aspects should be further investigated in future studies such as the use of fibrin to treat AF lesions as well as the mechanical properties of the fibrin-based biomaterials and of the neoformed tissue. Finally, in vivo studies and clinical trials with in situ injection of fibrin and human disc cells should be performed.
Alessandra Colombini1, Silvia Lopa, Cristina Ceriani, Arianna B Lovati, Samantha J Croiset, Alessia Di Giancamillo, Giovanni Lombardi, Giuseppe Banfi, Matteo Moretti
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.
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.
Comparison of Lumbar spineĀ Annulargramā¢Ā Ā and Lumbar SpineĀ MRIĀ . As shown: leaky discs are only visible on the Annulargramā¢
