Ronald J Midura

Cleveland Clinic · Department of Biomedical Engineering

The purpose of our study was to test the hypothesis that the electromagnetic pulse (EMP) is capable of inducing mechanical vibrations in bone ex vivo . A thin segment of human femur diaphysis (from a tissue repository) suspended on a tensioned line (range $T =$ 2.2–123 N) was exposed to EMP (mean $B =0.64$ T, dB / dt = 5877 T/s, and the me...

Objective: Clinical heterogeneity of primary osteoarthritis (OA) is a major challenge in understanding pathogenesis and development of targeted therapeutic strategies. This study aims to (1) identify OA patient subgroups phenotypes and (2) determine predictors of OA severity and cartilage-derived stem/progenitor concentration using clinical-, tiss...

Objective Glucose concentrations used in current cell culture methods are a significant departure from physiological glucose levels. The study focuses on comparing the effects of glucose concentrations on primary human progenitors (connective tissue progenitors [CTPs]) used for cartilage repair. Design Cartilage- (Outerbridge grade 1, 2, 3; superf...

Objective Evaluation of collagen orientation and arrangement in articular cartilage can improve our understanding of primary osteoarthritis (OA) progression and targeted therapies. Our goal was to determine if polarized light microscopy (PLM) for collagen organization is useful in identifying early primary OA features in comparison to current stand...

Osteoarthritis (OA) is a leading cause of disability in older adults and takes substantial toll at personal, economic and societal levels. ໿There is inadequate comprehension of OA disease progression specifically during the early phases of OA, which are critical to understanding the heterogeneity in OA progression as well as enable development of t...

Magnetic susceptibility of structurally intact bone may play a role in low frequency (below 10 kHz), low field (below 10 mT amplitude) pulsed electromagnetic field (LF PEMF) treatment of fracture non-unions and an adjunct to cervical fusion surgery, approved by the U.S Food and Drug Administration (FDA). The aim of this study was to determine if a...

Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1⁺ hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcanhdf lacks yolk sac vasculature, with at...

Pulsed electromagnetic field (PEMF) treatments stimulate bone formation activities though further work is needed to optimize its therapeutic benefit. PEMF can generate local potential gradients and electric currents that have been suggested to mimic bone electrochemical responses to load. In line with this reasoning, a recent publication reported t...

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpressi...

Chronic hypoxia leads to pathologic remodeling of the pulmonary vasculature and pulmonary hypertension (PH). The antioxidant enzyme extracellular superoxide dismutase (SOD3) protects against hypoxia-induced PH. Hyaluronan (HA), a ubiquitous glycosaminoglycan of the lung extracellular matrix, is rapidly recycled at sites of vessel injury and repair....

Background Cell-based therapy for cartilage repair is a promising approach and is becoming an established technique. Yet, there is no consensus on the optimal cell source. Purpose To provide a donor-matched quantitative comparison of the connective tissue progenitors (CTPs) derived from cartilage (Outerbridge grade 1-3 [G1-2-3]), bone marrow aspir...

Advanced-stage cancers often metastasize to bone, and is the major cause of cancer-related morbidity and mortality. Due to poor biodistribution of intravenously administered anticancer drugs within the bone, chemotherapy is not optimally effective in treating bone metastasis. Additionally, overexpression of receptor activator of nuclear factor κB l...

Extracellular matrix aggregates comprising the proteoglycan versican and glycosaminoglycan hyaluronan are necessary for cardiac development. Here we identify failure of primary vascular plexus formation and attenuation of primitive hematopoiesis in the yolk sac of the mouse insertional mutant Vcanhdf, which lacks all versican isoforms. Spatially co...

Objective: There is a clinical need to better characterize tissue-sources being used for stem cell therapies. This study focuses on comparison of cells and connective tissue progenitors (CTPs) derived from native human infrapatellar fatpad (IPFP), synovium (SYN), and periosteum (PERI). Design: IPFP, SYN, PERI were harvested from twenty-eight patien...

Background: Current decisions on cellular therapies for osteoarthritis are based primarily on clinical experience or on assumptions about preferred cell sourcing. They have not been informed by rigorous standardized measurements of the chondrogenic connective-tissue progenitors (CTP-Cs) or their intrinsic diversity of chondrogenic potential. The g...

Allergic asthma is a major cause of morbidity in both pediatric and adult patients. Recent research has highlighted the role of hyaluronan, an extracellular matrix glycosaminoglycan, in asthma pathogenesis. Experimental allergic airway inflammation and clinical asthma are associated with an increase of shorter fragments of hyaluronan (sHA), which c...

For many years, biologists have focused on the role of Pitx2, expressed on the left side of developing embryos, in governing organ laterality. Here, we identify a different pathway during left-right asymmetry initiated by the right side of the embryo. Surprisingly, this conserved mechanism is orchestrated by the extracellular glycosaminoglycan, hya...

Rationale: Dysregulated hyaluronan (HA) turnover is a newly recognized feature in multiple subgroups of pulmonary hypertension, including PH owing to chronic hypoxia. Extracellular superoxide dismutase (SOD3) protects against hypoxic PH. We hypothesized that hypoxia and vascular SOD3 availability determine the structure of pulmonary HA through regu...

Hyaluronan (HA), a high molecular weight non-sulfated glycosaminoglycan, is an integral component of the extracellular matrix of developing and mature connective tissues including tendon. There are few published reports quantifying HA content during tendon growth and maturation, or detailing its effects on the mechanical properties of the tendon ex...

Spinal cord injury (SCI) causes impaired neuronal function with associated deficits in the musculoskeletal system, which can lead to permanent disability. Here, the impact of SCI on in vivo musculoskeletal adaptation was determined by studying deficits in locomotor function and analyzing changes that occur in the muscle and bone compartments within...

Background aims: Connective tissue progenitors (CTPs) embody the heterogeneous stem and progenitor cell populations present in native tissue. CTPs are essential to the formation and remodeling of connective tissue and represent key targets for tissue-engineering and cell-based therapies. To better understand and characterize CTPs, we aimed to comp...

Cell-based therapies development for the treatment of osteoarthritis (OA) requires an understanding of the disease progression and attributes of the cells resident in cartilage. This study focused on quantitative assessment of the concentration and biological potential of stem and progenitor cells resident in different zones of cartilage displaying...

Background and purpose — A better understanding of the patterns and variation in initiation and progression of osteoarthritis (OA) in the knee may influence the design of therapies to prevent or slow disease progression. By studying cartilage from the human lateral femoral condyle (LFC), we aimed to: (1) assess specimen distribution into early, mil...

Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (AHR). TNF-stimulated gene 6 (TSG-6) is required to transfer inter-α-inhibitor heavy chains (HC) to hyaluronan (HA), facilitating HA receptors binding. TSG-6 is necessary for AHR in allergic asthma, because it facilitates the development of a pathological...

The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood. We show that the eukaryotic translation initiation factor eIF4E, an oncoprotein, drives H...

Objective: The two main objectives of the study include (1) Test the hypothesis that the lateral femoral condyle (LFC) in patients with primary OA and varus knees undergoing total knee arthroplasty (TKA) can be used as a model to better characterize varying histological features of human OA, (2) Correlate characteristic OA features using the estab...

Airway epithelium forms a barrier to the outside world and has a crucial role in susceptibility to viral infections. Cyclic adenosine monophosphate (cAMP) is an important second messenger acting via two intracellular signaling molecules: protein kinase A (PKA) and the guanidine nucleotide exchange factor, Epac. We sought to investigate effects of i...

Formation of cell surface protrusions has long been associated with tumor cell migration, metastasis & bone marrow homing & retention. It was shown that increased expression of endogenous or exogenous hyaluronic acid synthesizing enzyme 3 (HAS3) induces growth of microvillus-like cell surface protrusions. Some of the biological signals triggered by...

RATIONALE: Loss of extracellular superoxide dismutase (SOD3) contributes to chronic hypoxic pulmonary hypertension (PH) and injurious vascular remodeling. SOD3 preserves the structural integrity of lung matrix components, including glycans such as hyaluronan (HA). Fragments of HA are perceived in situ as inflammatory danger signals. We hypothesized...

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Hyaluronan (HA) exhibits numerous important roles in physiology and pathologies, and these facts necessitate an ability to accurately and reproducibly measure its quantities in tissues and cell cultures. Our group previously reported a rigorous and analytical procedure to quantify HA (and chondroitin sulfate, CS) using a reductive amination chemist...

The extracellular matrix glycosaminoglycan, hyaluronan, has been described as a regulator of tissue inflammation, with hyaluronan fragments reported to stimulate innate immune cells. High molecular mass hyaluronan is normally present in tissues, but upon inflammation lower molecular mass fragments are generated. It is unclear if these hyaluronan fr...

Objective: To determine the concentrations exhibiting toxicity of a cartilage-targeted magnetic resonance imaging contrast agent compared with gadopentetate dimeglumine (Gd-DT-PA) in chondrocyte cultures. Materials and methods: A long-term Swarm rat chondrosarcoma chondrocyte-like cell line was exposed for 48 h to 1.0-20 mM concentrations of dia...

Low-frequency (LF), low-amplitude alternating current (ac) magnetic fields are approved by the U.S. Food and Drug Administration as an adjunct to the orthopedic surgery procedure (spinal fusion surgery) and for the treatment of selected bone healing complications (fracture non-union). The biological effects are understood to rely on a contact-less...

Rationale: Hyaluronan (HA) has been used in treatment of CF via a nebulizer and has demonstrated success in clinical outcomes. HA is an important glycosaminoglycan that is crosslinked by heavy chains (HCs) from inter-alpha-inhibitor during inflammation. HC-HA becomes significantly more adhesive for leukocytes than non-cross-linked HA, which can en...

Electrical bone growth stimulators improve patient outcomes following the spinal fusion surgery, particularly important in high-risk patient populations. The therapeutic electromagnetic field (EMF) effects in tissue were modeled for two Food and Drug Administration (FDA) approved magnetic stimulation devices: 1) Coil A (SpinaLogic, DJO LLC, Vista,...

Transport of nutrients and waste across osseous tissue is dependent on the dynamic micro and macrostructure of the tissue; however little quantitative data exists examining how this transport occurs across the entire tissue. Here we investigate in vitro radial diffusion across a section of canine tissue, at dimensions of several hundred microns to...

Delayed bone healing has been noted in osteoporosis patients and in the ovariectomized (OVX) rat model of estrogen-depletion osteopenia. Pulsed electromagnetic field (PEMF) devices are clinically approved as an adjunct to cervical fusion surgery in patients at high risk for non-fusion and for the treatment of fracture non-unions. These bone growth...

Objective Contrast-enhanced magnetic resonance (MR) imaging methods have been proposed for non-invasive evaluation of osteoarthritis. We measured cell toxicities of cartilage-targeted low generation dendrimer-linked nitroxide MR contrast agents and gadopentetate dimeglumine (Gd-DTPA) on cultured chondrocytes. Design A long-term Swarm rat chondrosa...

Attachment and proliferation of UMR 106-01 osteosarcoma cells on nano-pitted and nano-textured surfaces of Ti-6Al-4V have been examined in the presence of bovine serum albumin (BSA) in order to mimic the very early stages of in vivo implantation, and to understand the role of nano-topography. The nano-pittted topography produced by anodization of t...

Isolated rat bone marrow stromal cells cultured in osteogenic medium in which the normal 5.6 mm glucose is changed to hyperglycemic 25.6 mm glucose greatly increase lipid formation between 21–31 days of culture that is associated with decreased biomineralization, up-regulate expression of cyclin D3 and two adipogenic markers (CCAAT/enhancer binding...

Fracture healing in animal models has been shown to be altered in both ground based analogs of spaceflight and in those exposed to actual spaceflight. The molecular mechanisms behind altered fracture healing as a result of chronic exposure to microgravity remain to be elucidated. This study investigates temporal gene expression of multiple factors...

The physiological adaptation of humans to harsh extracorporeal conditions such as those endured during space flight missions is incompletely understood and deserves considerably more attention to better comprehend and prepare space flight personnel for these alterations. Notable and well-documented changes include the loss of musculoskeletal homeos...

In long bone diaphyses, woven bone forms first and then transitions into a more mineralized compact bone tissue. Prior evidence suggests that the non-collagenous protein composition of woven bone may be distinct from that of more mature bone tissue, particularly with respect to a diverse group of phosphorylated, extracellular matrix proteins. To cr...

Homing of osteogenic cells through the systemic circulation represents an alternative to traditional orthopedic tissue engineering approaches that focus on local cell populations. We hypothesize that expression of the chemokine, stromal cell-derived factor-1 (SDF-1) or monocyte chemotactic protein-3 (MCP-3) may enhance homing of osteogenic cells in...

Mineralization, a characteristic phenotypic property of osteoblastic lineage cells, was blocked by 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) and decanoyl-Arg-Arg-Leu-Leu-chloromethyl ketone (dec-RRLL-cmk), inhibitors of SKI-1 (site 1; subtilisin kexin like-1) protease. Because SKI-1 is required for activation of SREBP and CREB...

The purpose of this study was to investigate the effect of differing storage medium on osteochondral plug diameter. Four storage conditions were evaluated: air, hypotonic solution (sterile water), isotonic saline solution (0.9% sodium chloride), and hypertonic saline solution (3.0% sodium chloride). Four osteochondral plugs were acquired (4.5-mm ha...

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A human mission to Mars will be physically demanding and will present a variety of risks to crew members. For a mission to be successful, crew members must remain healthy and able to complete a variety of tasks including launch and re-entry, system maintenance and repair, extravehicular activities, surface exploration, and in-flight and Mars surfac...

In vivo the hydraulic permeability of cortical bone influences the transport of nutrients, waste products and signaling molecules, thus influencing the metabolic functions of osteocytes and osteoblasts. In the current study two hypotheses were tested: the presence of (1) lipids and (2) collagen matrix in the porous compartment of cortical bone rest...

Bone sialoprotein (BSP), a small (approximately 80,000 M(r)) integrin binding, RGD-containing bone matrix glycoprotein, has been purified in milligram quantities from the serum-free medium of the rat osteosarcoma cell line UMR-106-BSP using nondenaturing conditions. Routine protein purification without serine protease inhibitors or reducing agents...

Daily injection of parathyroid hormone (PTH) is a clinically approved treatment for osteoporosis. It suppresses apoptosis of bone-forming osteoblasts although its exact anti-apoptotic mechanism(s) is incompletely understood. In this study, PTH treatment of cultured osteoblasts blocked the pro-apoptotic effects of serum withdrawal and nutrient depri...

The importance of the pathological changes in proteoglycans has driven the need to study and design novel chemical tools to control proteoglycan synthesis. Accordingly, we tested the fluorinated analogue of glucosamine (4-fluoro-N-acetyl-glucosamine (4-F-GlcNAc)) on the synthesis of heparan sulfate (HS) and chondroitin sulfate (CS) by murine airway...

Mineralization in UMR 106-01 osteoblastic cultures occurs within extracellular biomineralization foci (BMF) within 12 h after addition of beta-glycerol phosphate to cells at 64 h after plating. BMF are identified by their enrichment with an 85-kDa glycoprotein reactive with Maackia amurensis lectin. Laser Raman microspectroscopic scans were made on...

Calcium-containing spherical bodies (calcospherulites) exist along the mineralization front of bone and are thought to play a role in bone formation. Existing methods to isolate calcospherulites involve harsh treatments that remove much of their organic matter. This study sought to isolate them using a less destructive approach to better preserve t...

The biochemical mechanism controlling nucleation of mineral crystals in developing bone, along with the growth and propagation of these crystals once formed, remains poorly understood. To define the nucleation mechanism, a proteomics analysis was begun on isolated biomineralization foci (BMF), sites of initial crystal nucleation in osteoblastic cel...