Intervertebral disk repair by protein, gene, or cell injection: a framework for rehabilitation-focused biologics in the spine.

Low back pain carries an enormous socioeconomic burden. Current treatment modalities for symptomatic intervertebral disk (IVD) degeneration have limited and often inconsistent clinical benefits. Novel approaches with the potential to halt or even reverse disk degeneration and restore physiologic disk function, such as biological treatments, are therefore very attractive.

Transplantation of goat bone marrow stromal cells to the degenerating intervertebral disc in a goat disc injury model.

Study Design: randomized controlled study in the goat intervertebral disc (IVD) injury model.

Objective: To define the effects of allogeneic bone marrow-derived stromal cell injected into the degenerating goat IVDs.

Summary Of Background Data: Transplantation of bone marrow stromal cells to the degenerating disc has been suggested as a means to correct the biologic incompetence of the disc.

Primary bovine intervertebral disc cells transduced with adenovirus overexpressing 12 BMPs and Sox9 maintain appropriate phenotype.

Objective: To confirm that primary intervertebral disc cells cultured in monolayer transduced with adenovirus maintained their phenotype, hence is an appropriate system to test gene therapy agents.

Design: Adult bovine nucleus pulposus and anulus fibrosus cells cultured in monolayer were transduced with adenoviruses expressing human bone morphogenetic proteins (AdBMPs) or Sox9 (AdSox9), or green fluorescence protein (AdGFP, as control). Chondrocyte phenotypic markers (e.

Immunophenotypes of macular corneal dystrophy in India and correlation with mutations in CHST6.

Purpose: To determine the immunophenotypes of macular corneal dystrophy (MCD) in Indian patients and to correlate them with mutations in the carbohydrate 6-sulfotransferase (CHST6) gene.

Methods: Sixty-four patients from 53 families with MCD that were previously screened for mutations in CHST6 were included in an immunophenotype analysis. Antigenic keratan sulfate (AgKS) in serum as well as corneal tissue was evaluated in 31 families.

Age-related changes in the extracellular matrix of nucleus pulposus and anulus fibrosus of human intervertebral disc.

Study Design: To characterize age-related changes in the matrix of human intervertebral disc (IVD) specimens, human specimens from the third to the eighth decade of life were collected and analyzed for collagen and proteoglycan (PG) composition.

Objective: To identify age-related changes in the concentration of matrix macromolecules (collagen and PGs, including the small leucine-rich PGs biglycan, decorin, fibromodulin, and lumican) in human anulus fibrosus (AF) and nucleus pulposus (NP).

Summary Of Background Data: IVD degeneration is associated with changes in the concentration and fragmentation of matrix molecules.

Biological treatment for degenerative disc disease: implications for the field of physical medicine and rehabilitation.

Spine care is a fast-growing sector of the outpatient practice for physiatrists. Current nonsurgical treatment modalities and surgical options for severe symptomatic intervertebral disc degeneration have limited and inconsistent clinical results. Thus, the development of novel approaches, such as biological treatments that offer the potential to halt or even reverse disc degeneration and restore physiologic disc function, are very attractive.

Cell therapy using articular chondrocytes overexpressing BMP-7 or BMP-10 in a rabbit disc organ culture model.

Study Design: Rabbit knee articular chondrocytes overexpressing human growth factors were injected into cultured intervertebral disc explants. Survival of the injected cells and accumulation of extracellular matrix were assessed.

Objective: To define the utility of cell-based gene delivery approach for repair of the intervertebral disc.

Basic fibroblast growth factor accelerates matrix degradation via a neuro-endocrine pathway in human adult articular chondrocytes.

Pain-related neuropeptides released from synovial fibroblasts, such as substance P, have been implicated in joint destruction. Substance P-induced inflammatory processes are mediated via signaling through a G-protein-coupled receptor, that is, neurokinin-1 tachykinin receptor (NK(1)-R). We determined the pathophysiological link between substance P and its receptor in human adult articular cartilage homeostasis.

Regulation of immature cartilage growth by IGF-I, TGF-beta1, BMP-7, and PDGF-AB: role of metabolic balance between fixed charge and collagen network.

Cartilage growth may involve alterations in the balance between the swelling tendency of proteoglycans and the restraining function of the collagen network. Growth factors, including IGF-I, TGF-beta1, BMP-7, and PDGF-AB, regulate chondrocyte metabolism and, consequently, may regulate cartilage growth. Immature bovine articular cartilage explants from the superficial and middle zones were incubated for 13 days in basal medium or medium supplemented with serum, IGF-I, TGF-beta1, BMP-7, or PDGF-AB.

Effect of osteogenic protein-1 on the matrix metabolism of bovine tendon cells.

Tendon rupture is a common sports injury in adults. However, the mechanical properties of repair tissue are inferior to those of normal tissue. To accelerate tendon healing, an in vivo approach using growth factors has been applied and has shown evidence for the efficacy of biological stimulation of the repair process.

Recombinant human osteogenic protein-1 upregulates proteoglycan metabolism of human anulus fibrosus and nucleus pulposus cells.

Study Design: In vitro assessment of the effects of recombinant human osteogenic protein-1 (rhOP-1) on the proteoglycan metabolism of human intervertebral disc cells.

Objectives: To determine whether rhOP-1 is effective in stimulating the cell proliferation and proteoglycan metabolism of human intervertebral disc cells cultured in alginate beads.

Summary Of The Background Data: OP-1 has been shown to stimulate the proteoglycan and collagen synthesis of rabbit intervertebral disc cells in vitro.

Mechanisms of cartilage growth: modulation of balance between proteoglycan and collagen in vitro using chondroitinase ABC.

Objective: To examine the cartilage growth-associated effects of a disruption in the balance between the swelling pressure of glycosaminoglycans (GAGs) and the restraining function of the collagen network, by diminishing GAG content prior to culture using enzymatic treatment with chondroitinase ABC.

Methods: Immature bovine articular cartilage explants from the superficial and middle layers were analyzed immediately or after incubation in serum-supplemented medium for 13 days. Other explants were treated with chondroitinase ABC to deplete tissue GAG and also either analyzed immediately or after incubation in serum-supplemented medium for 13 days.

Comparative effects of bone morphogenetic proteins and sox9 overexpression on extracellular matrix metabolism of bovine nucleus pulposus cells.

Study Design: An in vitro biologic study of the effects of adenovirus expressing bone morphogenetic proteins (BMPs) and adenovirus expressing Sox9 on extracellular matrix metabolism by bovine nucleus pulposus cells.

Objective: To compare the effects of recombinant adenoviral vectors expressing various BMPs (2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 14, and 15) and Sox9 on extracellular matrix accumulation by bovine nucleus pulposus cells.

Summary Of Background Data: Nucleus pulposus matrix production may be promoted by transducing the cells with genes that permit the sustained expression of growth factors.

Tracking chondrocytes and assessing their proliferation with PKH26: effects on secretion of proteoglycan 4 (PRG4).

Distinguishing between implanted and host-derived cells, as well as between distinct cell phenotypes, would be useful in assessing the mechanisms of cell-based repair of cartilage. The fluorescent tracker dye, PKH26, was previously applied to several cell types to assess proliferation in vitro and to track cells in vivo. The objectives of this study were to assess the utility of PKH26 for tracking chondrocytes from superficial and middle zones and their proliferation, and determine the effects of PKH26 on chondrocyte functions, in particular, proliferation and secretion of Proteoglycan 4 (PRG4).

Osteogenic protein 1 in synovial fluid from patients with rheumatoid arthritis or osteoarthritis: relationship with disease and levels of hyaluronan and antigenic keratan sulfate.

The measurement of body fluid levels of biochemical markers in joint tissues has begun to provide clinically useful information. Synovial fluid (SF) plays an important role in articular joint lubrication, nutrition, and metabolism of cartilage and other connective tissues within the joint. The purpose of our study was to identify and characterize osteogenic protein 1 (OP-1) in SF from patients with rheumatoid arthritis (RA) or with osteoarthritis (OA) and to correlate levels of OP-1 with those of hyaluronan (HA) and antigenic keratan sulfate (AgKS).

Platelet-rich plasma (PRP) stimulates the extracellular matrix metabolism of porcine nucleus pulposus and anulus fibrosus cells cultured in alginate beads.

Study Design: In vitro assessment of the effects of platelet-rich plasma on the extracellular matrix metabolism of porcine intervertebral disc cells.

Objectives: To determine whether platelet-rich plasma is effective in stimulating cell proliferation and extracellular matrix metabolism by porcine disc cells cultured in alginate beads.

Summary Of Background Data: Platelet-rich plasma is used to accelerate wound healing and tissue regeneration.

Serum and synovial fluid concentrations of keratan sulfate and hyaluronan in dogs with induced stifle joint osteoarthritis following cranial cruciate ligament transection.

Objective: To examine longitudinal changes in serum and synovial fluid concentrations of keratan sulfate (KS) and hyaluronan (HA) after cranial cruciate ligament (CCL) transection in dogs.

Animals: 12 clinically normal adult mixed-breed dogs.

Procedure: Following CCL transection in the right stifle joint, KS and HA concentrations were determined in serum and neat (undiluted) synovial fluid prior to and 1, 2, 3, and 12 months after surgery.

Transduced bovine articular chondrocytes affect the metabolism of cocultured nucleus pulposus cells in vitro: implications for chondrocyte transplantation into the intervertebral disc.

Study Design: Biologic study on the effects of coculture of bovine articular chondrocytes transduced ex vivo with genes expressing bone morphogenetic proteins (BMPs) on nucleus pulposus (NP) cells.

Objective: To evaluate the effects of bovine articular chondrocytes transduced with adenoviruses expressing various BMPs on proteoglycan and collagen production, and cellular proliferation of NP cells in vitro.

Summary Of Background Data: Matrix synthesis by intervertebral disc cells is promoted by exposing the cells to growth factors or delivering genes that permit sustained expression of growth factors.

Exposure to pulsed low intensity ultrasound stimulates extracellular matrix metabolism of bovine intervertebral disc cells cultured in alginate beads.

Study Design: In vitro study on the effects of pulsed low intensity ultrasound on the cellular metabolism of bovine intervertebral disc cells.

Objective: To determine whether pulsed low intensity ultrasound has effects on cell proliferation and extracellular matrix metabolism by bovine intervertebral disc cells.

Summary Of Background Data: The application of pulsed low intensity ultrasound is known to be effective in stimulating fracture and cartilage repair.

Characterization of human nasal septal chondrocytes cultured in alginate.

Background: After serial passages in monolayer, chondrocytes dedifferentiate into a fibroblast-like phenotype. Our objective was to determine if culture in alginate affects the phenotype of dedifferentiated human nasal septal chondrocytes.

Study Design: Human nasal septal chondrocytes were seeded at low density and passaged in monolayer culture.

Low-dose interleukin-1 partially counteracts osteogenic protein-1-induced proteoglycan synthesis by adult bovine intervertebral disk cells.

Objective: Low back pain associated with degenerative disk disease is a common clinical problem that has enormous socioeconomic impact in today's aging population. As an alternative to the surgical removal of the diseased intervertebral disk, the direct application of a purified growth factor into the intervertebral disk may provide physiatrists a valuable tool to halt or slow down disk degeneration. Our goal here is to determine if low levels of interleukin-1 (IL-1), a proinflammatory cytokine present in the degenerating disk, could interfere with the potentially beneficial effects of growth factors on proteoglycan synthesis.

Differential effects of fibronectin fragment on proteoglycan metabolism by intervertebral disc cells: a comparison with articular chondrocytes.

Study Design: This in vitro study used the alginate bead culture system to probe for differences in the effects of fibronectin fragment on cell proliferation and proteoglycan metabolism by different populations of intervertebral disc cells and articular chondrocytes.

Objective: To compare the effects of fibronectin fragment on cell proliferation, and proteoglycan synthesis and degradation by cells from the nucleus pulposus, the anulus fibrosus, and articular cartilage.

Summary Of Background Data: In articular cartilage, the administration of fibronectin fragment stimulates cartilage degeneration.

Intradiscal administration of osteogenic protein-1 increases intervertebral disc height and proteoglycan content in the nucleus pulposus in normal adolescent rabbits.

Study Design: A study of the disc height and biochemical changes in the rabbit intervertebral disc after injection of osteogenic protein-1 into the nucleus pulposus.

Objectives: To evaluate the in vivo effects of osteogenic protein-1 administered intradiscally to the intervertebral disc of rabbits.

Summary Of Background Data: Growth factors, such as osteogenic protein-1 and transforming growth factor-beta, have the ability to stimulate synthesis of proteoglycan and collagen in vitro.

Treatment with calcitonin prevents the net loss of collagen, hyaluronan and proteoglycan aggregates from cartilage in the early stages of canine experimental osteoarthritis.

Objective: To evaluate the effect of calcitonin (CT) on the histology and biochemistry of articular cartilage from unstable operated and nonoperated knee in a canine model of experimental osteoarthritis (OA).

Methods: Eighteen dogs underwent anterior cruciate ligament transection (ACLT) of the right knee and were randomly distributed into three groups of six dogs each. From day-1 after surgery until sacrifice 84 days post-ACLT, each dog received a daily nasal spray that delivered the placebo, 100 units of CT or 400 units of CT.