Rehabilitation Medicine Research Center

Rochester, MN, United States

Rehabilitation Medicine Research Center

Rochester, MN, United States
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Grodzinsky A.J.,Massachusetts Institute of Technology | Wang Y.,Massachusetts Institute of Technology | Kakar S.,Mayo Medical School | Vrahas M.S.,Harvard University | Evans C.H.,Rehabilitation Medicine Research Center
Journal of Orthopaedic Research | Year: 2017

Injury to the joint provokes a number of local pathophysiological changes, including synthesis of inflammatory cytokines, death of chondrocytes, breakdown of the extra-cellular matrix of cartilage, and reduced synthesis of matrix macromolecules. These processes combine to engender the subsequent development of post-traumatic osteoarthritis (PTOA). To prevent this from happening, it is necessary to inhibit these disparate responses to injury; given their heterogeneity, this is challenging. However, dexamethasone has the necessary pleiotropic properties required of a drug for this purpose. Using in vitro models, we have shown that low doses of dexamethasone sustain the synthesis of cartilage proteoglycans while inhibiting their breakdown after injurious compression in the presence or absence of inflammatory cytokines. Under these conditions, dexamethasone is non-toxic and maintains the viability of chondrocytes exposed chronically to such cytokines as interleukin (IL) -1, IL-6, and tumor necrosis factor-α. Moreover, the anti-inflammatory properties of dexamethasone have been appreciated for decades. In view of this information, we have initiated a pilot clinical study to determine whether a single, intra-articular injection of dexamethasone into the wrist shows promise in preventing PTOA after intra-articular fracture of the distal radius. CLINICAL SIGNIFICANCE: Suppressing the various etiopathophysiological responses to injury in the joint is an attractive strategy for lowering the clinical burden of PTOA. The intra-articular administration of dexamethasone soon after injury offers a simple and inexpensive means of accomplishing this. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:406–411, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Docheva D.,Ludwig Maximilians University of Munich | Muller S.A.,University of Basel | Majewski M.,University of Basel | Evans C.H.,Rehabilitation Medicine Research Center
Advanced Drug Delivery Reviews | Year: 2015

Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management. © 2014.

Cloud B.A.,Rochester College | Zhao K.D.,Rehabilitation Medicine Research Center
Gait and Posture | Year: 2014

Spinal posture affects how individuals function from a manual wheelchair. There is a need to directly quantify spinal posture in this population to ultimately improve function. A fiber optic system, comprised of an attached series of sensors, is promising for measuring large regions of the spine in individuals sitting in a wheelchair. The purpose of this study was to determine the agreement between fiber optic and optoelectronic systems for measuring spinal curvature, and describe the range of sagittal plane spinal curvatures in natural sitting. Able-bodied adults (n=26, 13 male) participated. Each participant assumed three sitting postures: natural, slouched (accentuated kyphosis), and extension (accentuated lordosis) sitting. Fiber optic (ShapeTape) and optoelectronic (Optotrak) systems were applied to the skin over spinous processes from S1 to C7 and used to measure sagittal plane spinal curvature. Regions of kyphosis and lordosis were identified. A Cobb angle-like method was used to quantify lordosis and kyphosis. Generalized linear model and Bland-Altman analyses were used to assess agreement. A strong correlation exists between curvature values obtained with Optotrak and ShapeTape (R2=0.98). The mean difference between Optotrak and ShapeTape for kyphosis in natural, extension, and slouched postures was 4.30° (95% LOA: -3.43 to 12.04°), 3.64° (95% LOA: -1.07 to 8.36°), and 4.02° (95% LOA: -2.80 to 10.84°), respectively. The mean difference for lordosis, when present, in natural and extension postures was 2.86° (95% LOA: -1.18 to 6.90°) and 2.55° (95% LOA: -3.38 to 8.48°), respectively. In natural sitting, the mean±SD of kyphosis values was 35.07±6.75°. Lordosis was detected in 8/26 participants: 11.72±7.32°. The fiber optic and optoelectronic systems demonstrate acceptable agreement for measuring sagittal plane thoracolumbar spinal curvature. © 2014 Elsevier B.V.

Evans C.,Rehabilitation Medicine Research Center | Evans C.,Collaborative Research Center
International Orthopaedics | Year: 2014

Traditional tissue engineering approaches to the restoration of orthopaedic tissues promise to be expensive and not well suited to treating large numbers of patients. Advances in gene transfer technology offer the prospect of developing expedited techniques in which all manipulations can be performed percutaneously or in a single operation. This rests on the ability of gene delivery to provoke the sustained synthesis of relevant gene products in situ without further intervention. Regulated gene expression is also possible, but its urgency is reduced by our ignorance of exactly what levels and periods of expression are needed for specific gene products. This review describes various strategies by which gene therapy can be used to expedite the repair and regeneration of orthopaedic tissues. Strategies include the direct injection of vectors into sites of injury, the use of genetically modified, allogeneic cell lines and the intra-operative harvest of autologous tissues that are quickly transduced and returned to the body, either intact or following rapid cell isolation. Data obtained from pre-clinical experiments in animal models have provided much encouragement that such approaches may eventually find clinical application in human and veterinary medicine. © 2014 SICOT aisbl.

Pleticha J.,Oncology and the Cancer Center | Heilmann L.F.,Oncology and the Cancer Center | Evans C.H.,Rehabilitation Medicine Research Center | Asokan A.,University of North Carolina at Chapel Hill | And 2 more authors.
Molecular Pain | Year: 2014

Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting. © 2014 Pleticha et al.; licensee BioMed Central Ltd.

Bara J.J.,AO Research Institute Davos | Herrmann M.,AO Research Institute Davos | Evans C.H.,Rehabilitation Medicine Research Center | Miclau T.,San Francisco General Hospital | And 2 more authors.
Journal of Orthopaedic Research | Year: 2016

There is a clear discrepancy between the growth of cell therapy and tissue engineering research in orthopaedics over the last two decades and the number of approved clinical therapies and products available to patients. At the 2015 annual meeting of the Orthopaedic Research Society, a workshop was held to highlight important considerations from the perspectives of an academic scientist, clinical researcher, and industry representative with the aim of helping researchers to successfully translate their ideas into clinical and commercial reality. Survey data acquired from workshop participants indicated an overall positive opinion on the future potential of cell-based therapies to make a significant contribution to orthopaedic medicine. The survey also indicated an agreement on areas requiring improvement in the development of new therapies, specifically; increased support for fundamental research and education and improved transparency of regulatory processes. This perspectives article summarises the content and conclusions of the workshop and puts forward suggestions on how translational success of cell-based therapies in orthopaedics may be achieved. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Evans C.H.,Rehabilitation Medicine Research Center | Evans C.H.,AO Research Institute Davos
Annals of Biomedical Engineering | Year: 2015

Much effort is expended in developing biomimetic scaffolds that provide the micro-architecture of native tissue with appropriate cellular niches. Such scaffolds are often seeded with progenitor cells to generate engineered replacements for diseased or damaged tissues. An alternative approach relies on biology, rather than technology, to provide scaffolds containing progenitor cells in authentic niches. This article describes the use of accessible living tissues containing endogenous progenitor cells in their native, physiological environments. Such tissues also possess scaffolding properties, and can be readily harvested, manipulated and returned to the patient intra-operatively to facilitate repair and regeneration. Our group has explored the in situ genetic manipulation of cells within these tissues before they are reimplanted, although other means of modulation are certainly possible. Examples of suitable donor tissues include marrow, skeletal muscle and fat. In the case of marrow, clotting produces a moldable, autologous fibrin matrix containing endogenous cells; if necessary, exogenous cells can be added prior to clotting. These approaches have been studied experimentally in orthopaedic contexts, particularly for the healing and regeneration of bone and cartilage. © 2014, Biomedical Engineering Society.

Evans C.H.,Rehabilitation Medicine Research Center | Huard J.,University of Pittsburgh
Nature Reviews Rheumatology | Year: 2015

Injuries to the musculoskeletal system are common, debilitating and expensive. In many cases, healing is imperfect, which leads to chronic impairment. Gene transfer might improve repair and regeneration at sites of injury by enabling the local, sustained and potentially regulated expression of therapeutic gene products; such products include morphogens, growth factors and anti-inflammatory agents. Proteins produced endogenously as a result of gene transfer are nascent molecules that have undergone post-translational modification. In addition, gene transfer offers particular advantages for the delivery of products with an intracellular site of action, such as transcription factors and noncoding RNAs, and proteins that need to be inserted into a cell compartment, such as a membrane. Transgenes can be delivered by viral or nonviral vectors via in vivo or ex vivo protocols using progenitor or differentiated cells. The first gene transfer clinical trials for osteoarthritis and cartilage repair have already been completed. Various bone-healing protocols are at an advanced stage of development, including studies with large animals that could lead to human trials. Other applications in the repair and regeneration of skeletal muscle, intervertebral disc, meniscus, ligament and tendon are in preclinical development. In addition to scientific, medical and safety considerations, clinical translation is constrained by social, financial and logistical issues. © 2015 Macmillan Publishers Limited. All rights reserved.

Panos M.,Mayo Medical School | Christophi G.P.,Mayo Medical School | Rodriguez M.,Rehabilitation Medicine Research Center | Scarisbrick I.A.,Mayo Medical School | Scarisbrick I.A.,Rehabilitation Medicine Research Center
Biological Chemistry | Year: 2014

Recent studies provide a functional link between kallikrein 6 (Klk6) and the development and progression of disease in patients with multiple sclerosis (MS) and in its murine models. To evaluate the involvement of additional kallikrein family members, we compared Klk6 expression with four other kallikreins (Klk1, Klk7, Klk8, and Klk10) in the brain and spinal cord of mice infected with Theiler's murine encephalomyelitis virus, an experimental model of progressive MS. The robust upregulation of Klk6 and Klk8 in the brain during the acute phase of viral encephalitis and in the spinal cord during disease development and progression points to their participation in inflammation, demyelination, and progressive axon degeneration. More limited changes in Klk1, Klk7, and Klk10 were also observed. In addition, Klk1, Klk6, and Klk10 were dynamically regulated in T cells in vitro as a recall response to viral antigen and in activated monocytes, pointing to their activities in the development of adaptive and innate immune function. Together, these results point to overlapping and unique roles for multiple kallikreins in the development and progression of virusmediated central nervous system inflammatory demyelinating disease, including activities in the development of the adaptive and innate immune response, in demyelination, and in progressive axon degeneration. © 2015, WDG. All rights reserved.

Yoon H.,Mayo Medical School | Yoon H.,Rehabilitation Medicine Research Center | Radulovic M.,Rehabilitation Medicine Research Center | Radulovic M.,Mayo Medical School | And 5 more authors.
GLIA | Year: 2015

Hemorrhagic white matter injuries in the perinatal period are a growing cause of cerebral palsy yet no neuroprotective strategies exist to prevent the devastating motor and cognitive deficits that ensue. We demonstrate that the thrombin receptor (protease-activated receptor 1, PAR1) exhibits peak expression levels in the spinal cord at term and is a critical regulator of the myelination continuum from initiation to the final levels achieved. Specifically, PAR1 gene deletion resulted in earlier onset of spinal cord myelination, including substantially more Olig2-positive oligodendrocytes, more myelinated axons, and higher proteolipid protein (PLP) levels at birth. In vitro, the highest levels of PAR1 were observed in oligodendrocyte progenitor cells (OPCs), being reduced with differentiation. In parallel, the expression of PLP and myelin basic protein (MBP), in addition to Olig2, were all significantly higher in cultures of PAR1-/- oligodendroglia. Moreover, application of a small molecule inhibitor of PAR1 (SCH79797) to OPCs in vitro increased PLP and MBP expression. Enhancements in myelination associated with PAR1 genetic deletion were also observed in adulthood as evidenced by higher amounts of MBP and thickened myelin sheaths across large, medium, and small diameter axons. Enriched spinal cord myelination in PAR1-/- mice was coupled to increases in extracellular-signal-regulated kinase 1/2 and AKT signaling developmentally. Nocturnal ambulation and rearing activity were also elevated in PAR1-/- mice. These studies identify the thrombin receptor as a powerful extracellular regulatory switch that could be readily targeted to improve myelin production in the face of white matter injury and disease. © 2015 Wiley Periodicals, Inc.

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