fibrin and Intervertebral-Disc-Degeneration

With the aging population, it is clear that the demand for future chronic pain treatment modalities is at an all-time high. One of the newest treatment modalities that is gaining popularity with both practitioners and patients alike is that of regenerative medicine and the use of stem cells to treat chronic painful conditions. This article aims to distill the most recent, available data from both laboratory research and clinical trials to better illuminate the potentials for these therapies in the treatment of chronic pain.. There are numerous investigations underway using mesenchymal stem cells (MSCs) to treat painful, largely degenerative conditions. A large majority of these investigations focus on osteoarthritis of the knee and have demonstrated significantly improved pain scores. Some of these investigations have demonstrated significantly increased articular cartilage and meniscus growth as well as improved function. These studies have been smaller (n, 18) and need to be corroborated on a macrolevel. Platelet-rich plasma (PRP)-based therapies have been most extensively studied in the treatment of knee osteoarthritis. Multiple prospective and randomized trials and meta-analyses have afforded level I evidence in support of PRP's safety and efficacy in chronic knee pain demonstrating both decreased pain (via VAS) and increased functional status (via WOMAC and IKDC). There have been randomized controlled trials examining PRP therapies in treatment degenerative disc disease (intradiscal treatment), facet arthropathy (intra-facet injections), and sacroiliitis (SIJ) which have all yielded similar positive results. Each RTC demonstrated decreased pain scores and increased function but lacks the scale to derive concrete guidelines. Newer investigations are underway examining modified PRP formulas with increased fibrin (PRF) or various growth factors (PRGF) and have shown positive outcomes with respect to osteoarthritic conditions in small trials. Animal trials are underway further investigating these therapies as well as specific gene modulation therapies. This review of the most recent investigations into the application and uses of biologic stem cell-derived treatments for chronic painful conditions should act to illustrate the growing, favorable data for these types of modalities both with respect to pain control and functional improvement.

Topics: Biological Therapy; Chronic Pain; Fibrin; Humans; Intercellular Signaling Peptides and Proteins; Intervertebral Disc Degeneration; Joint Diseases; Mesenchymal Stem Cell Transplantation; Osteoarthritis, Knee; Platelet-Rich Plasma; Sacroiliitis; Zygapophyseal Joint

Discectomy procedures alleviate disability caused by intervertebral disc (IVD) herniation, but do not repair herniation-induced annulus fibrosus (AF) defects. Cell therapy shows promise for IVD repair, yet cell delivery biomaterials capable of sealing AF defects and restoring biomechanical function have poor biological performance. To balance the biomechanical and biological demands of IVD cell delivery biomaterials, we engineered an injectable composite biomaterial using cell-laden, degradable oxidized alginate (OxAlg) microbeads (MBs) to deliver AF cells within high-modulus genipin-crosslinked fibrin (FibGen) hydrogels (FibGen + MB composites). Conceptually, the high-modulus FibGen would immediately stabilize injured IVDs, while OxAlg MBs would protect and release cells required for long-term healing. We first showed that AF cells microencapsulated in OxAlg MBs maintained high viability and, upon release, displayed phenotypic AF cell morphology and gene expression. Next, we created cell-laden FibGen + MB composites and demonstrated that OxAlg MBs functionalized with RGD peptides (MB-RGD) minimized AF cell apoptosis and retained phenotypic gene expression. Further, we showed that cell-laden FibGen + MB composites are biomechanically stable and promote extracellular matrix (ECM) synthesis in long-term in vitro culture. Lastly, we evaluated cell-laden FibGen + MB-RGD composites in a long-term bovine caudal IVD organ culture bioreactor and found that composites had low herniation risk, provided superior biomechanical and biological repair to discectomy controls, and retained anabolic cells within the IVD injury space. This novel injectable composite hydrogel strategy shows promise as an IVD cell delivery sealant with potentially broad applications for its capacity to balance biomechanical and biological performance.

Topics: Animals; Biocompatible Materials; Cattle; Fibrin; Hydrogels; Intervertebral Disc; Intervertebral Disc Degeneration; Microspheres; Oligopeptides

Growth of nerve fibers has been shown to occur in a rabbit model of intravertebral disc degeneration (IVD) induced by needle puncture. As nerve growth may underlie the process of chronic pain in humans affected by disc degeneration, we sought to investigate the factors underlying nerve ingrowth in a minimally invasive annulotomy rabbit model of IVD by comparing the effects of empty disc defects with those of defects filled with poly(lactic-co-glycolic acid)/fibrin gel (PLGA) plugs.. New Zealand white rabbits (n = 24) received annular injuries at three lumbar levels (L3/4, L4/5, and L5/6). The discs were randomly assigned to four groups: (a) annular defect (1.8-mm diameter; 4-mm depth) by mini-trephine, (b) annular defect implanted with a PLGA scaffold containing a fibrin gel, (c) annular puncture by a 16G needle (5-mm depth), and (d) uninjured L2/3 disc (control). Disc degeneration was evaluated by radiography, MRI, histology, real-time PCR, and analysis of proteoglycan (PG) content. Nerve ingrowth into the discs was assessed by immunostaining with the nerve marker protein gene product 9.5.. Injured discs showed a progressive disc space narrowing with significant disc degeneration and proteoglycan loss, as confirmed by imaging results, molecular and compositional analysis, and histological examinations. In 16G punctured discs, nerve ingrowth was observed on the surface of scar tissue. In annular defects, nerve fibers were found to be distributed along small fissures within the fibrocartilaginous-like tissue that filled the AF. In discs filled with PLGA/ fibrin gel, more nerve fibers were observed growing deeper into the inner AF along the open annular track.  In addition, innervations scores showed significantly higher than those of punctured discs and empty defects. A limited vascular proliferation was found in the injured sites and regenerated tissues.. Nerve ingrowth was significantly higher in PLGA/fibrin-filled discs than in empty defects. Possible explanations include (i) annular fissures along the defect and early loss of proteoglycan may facilitate the ingrowth process and (ii) biodegradable PLGA/fibrin gel may promote adverse growth of nerves and blood vessels into deeper parts of injured disc. The rabbit annular defect model of disc degeneration appears suitable to investigate the effects of nerve ingrowth in relation to pain generation.

Topics: Animals; Disease Models, Animal; Fibrin; Gels; Intervertebral Disc Degeneration; Lactic Acid; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rabbits; Random Allocation; Tissue Scaffolds; Treatment Outcome

To develop a biomimetic polymeric injectable hydrogel that can support nucleus pulposus (NP) regeneration.. Natural polymer-based hydrogels were synthesized using fibrinogen (FBG) and hyaluronic acid (HA), conjugated by a novel two-step procedure. Bovine NP cells were cultured in FBG-HA conjugate-based 3D beads in vitro and in a nucleotomized organ culture model.. FBG-HA conjugate-based hydrogels prepared with 235 KDa HA at a FBG/HA w/w ratio of 17:1 showed superior gel stability and mechanical properties and markedly increased glycosaminoglycan synthesis compared with a FBG/HA mixture-based hydrogels or fibrin gels. Gene-expression levels of NP markers were maintained in vitro. In organ culture, NP cells seeded in FBG-HA conjugate-based hydrogels showed better integration with native NP tissue compared with fibrin gels. Moreover, FBG-HA conjugate-based hydrogels restored compressive stiffness and disc height after nucleotomy under dynamic load.. Specific FBG-HA conjugate-based hydrogels may be suitable as injectable materials for minimally invasive, biological NP regeneration.

Topics: Animals; Biomechanical Phenomena; Biomimetic Materials; Cattle; Cells, Cultured; Chromatography, Liquid; Fibrin; Gene Expression Profiling; Histological Techniques; Hyaluronic Acid; Hydrogels; Intervertebral Disc; Intervertebral Disc Degeneration; Regeneration; Statistics, Nonparametric