Publication of the Month 2010

Title: The emerging relationship between regenerative medicine and physical therapeutics.

Summary: Dramatic changes in the health care landscape over the next few decades undoubtedly will affect rehabilitation specialists’ practice. In the multidisciplinary field of regenerative medicine, cell, tissue, or organ substitutes are used to enhance the healing potential of the body. Given that the restoration of normal functioning of injured or diseased tissues is expected to be the ultimate goal of these therapies, the future of regenerative medicine is, undeniably, tightly intertwined with that of rehabilitation. Rehabilitation specialists not only must be aware of cutting-edge medical advances as they relate to regenerative medicine but also must work closely with basic scientists to guide the development of clinically relevant protocols. The purposes of this article are to provide a current perspective on biological approaches to the management of musculoskeletal disorders and to highlight the needed integration of physical therapeutics with regenerative medicine.

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Title: Optical coherence tomography detection of subclinical traumatic cartilage injury.

Summary: OBJECTIVES: Posttraumatic arthritis is a major cause of disability. Current clinical imaging modalities are unable to reliably evaluate articular cartilage damage before surface breakdown, when potentially reversible changes are occurring. Optical coherence tomography (OCT) is a nondestructive imaging technology that can detect degenerative changes in articular cartilage with an intact surface. This study tests the hypothesis that OCT detects acute articular cartilage injury after impact at energy levels resulting in chondrocyte death and microstructural changes, but insufficient to produce macroscopic surface damage.

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Title: Pericyte-based human tissue engineered vascular grafts

Summary: The success of small-diameter tissue engineered vascular grafts (TEVGs) greatly relies on an appropriate cell source and an efficient cellular delivery and carrier system. Pericytes have recently been shown to express mesenchymal stem cell features. Their relative availability and multipotentiality make them a promising candidate for TEVG applications. The objective of this study was to incorporate pericytes into a biodegradable scaffold rapidly, densely and efficiently, and to assess the efficacy of the pericyte-seeded scaffold in vivo. Bi-layered elastomeric poly(ester-urethane)urea scaffolds (length = 10 mm; inner diameter = 1.3 mm) were bulk seeded with 3 x 10(6) pericytes using a customized rotational vacuum seeding device in less than 2 min (seeding efficiency > 90%). The seeded scaffolds were cultured in spinner flasks for 2 days and then implanted into Lewis rats as aortic interposition grafts for 8 weeks. Results showed pericytes populated the porous layer of the scaffolds evenly and maintained their original phenotype after the dynamic culture. After implantation, pericyte-seeded TEVGs showed a significant higher patency rate than the unseeded control: 100% versus 38% (p < 0.05). Patent pericyte-seeded TEVGs revealed extensive tissue remodeling with collagen and elastin present. The remodeled tissue consisted of multiple layers of alpha-smooth muscle actin- and calponin-positive cells, and a von Willebrand factor-positive monolayer in the lumen. These results demonstrate the feasibility of a pericyte-based TEVG and suggest that the pericytes play a role in maintaining patency of the TEVG as an arterial conduit.

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Title: Regulation of the autophagy protein LC3 by phosphorylation

Summary: Macroautophagy is a major catabolic pathway that impacts cell survival, differentiation, tumorigenesis, and neurodegeneration. Although bulk degradation sustains carbon sources during starvation, autophagy contributes to shrinkage of differentiated neuronal processes. Identification of autophagy-related genes has spurred rapid advances in understanding the recruitment of microtubule-associated protein 1 light chain 3 (LC3) in autophagy induction, although braking mechanisms remain less understood. Using mass spectrometry, we identified a direct protein kinase A (PKA) phosphorylation site on LC3 that regulates its participation in autophagy. Both metabolic (rapamycin) and pathological (MPP(+)) inducers of autophagy caused dephosphorylation of endogenous LC3. The pseudophosphorylated LC3 mutant showed reduced recruitment to autophagosomes, whereas the nonphosphorylatable mutant exhibited enhanced puncta formation. Finally, autophagy-dependent neurite shortening induced by expression of a Parkinson disease-associated G2019S mutation in leucine-rich repeat kinase 2 was inhibited by dibutyryl-cyclic adenosine monophosphate, cytoplasmic expression of the PKA catalytic subunit, or the LC3 phosphorylation mimic. These data demonstrate a role for phosphorylation in regulating LC3 activity.

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Title: Cancerous stem cells: deviant stem cells with cancer-causing misbehavior

Summary: Stem cells maintain homeostasis in adult tissues via self-renewal and generation of terminally differentiated cells. Alterations in this intricate balance can result in disease. It has become increasingly evident that cancer can be initiated at the level of stem cells. Therefore, understanding what causes stem cells to become cancerous may lead to new therapeutic approaches. Multiple signaling pathways ultimately affect stem cell survival and proliferation, thus maintaining homeostasis in the gut. Changes in these pathways could perturb normal stem cell behavior, leading to cancerous stem cells. In addition, cancerous stem cells show resistance to current therapies and may lead to a dangerous selection process resulting in recurrence and metastasis. Genomic instability, the driving force of mutation and resistance, may give cancerous stem cells an adaptive advantage, especially when subjected to cancer therapies. Targeting the unique characteristics of cancerous stem cells to promote either terminal differentiation or destruction would effectively eradicate cancer and improve patient care and survival.

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Title: Nucleotide-Binding Oligomerization Domain-2 Inhibits Toll-Like Receptor-4 Signaling in the Intestinal Epithelium.

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Title: PediaFlow Maglev Ventricular Assist Device: A Prescriptive Design Approach

Summary: This report describes a multi-disciplinary program to develop a pediatric blood pump, motivated by the critical need to treat infants and young children with congenital and acquired heart diseases. The unique challenges of this patient population require a device with exceptional biocompatibility, miniaturized for implantation up to 6 months. This program implemented a collaborative, prescriptive design process, whereby mathematical models of the governing physics were coupled with numerical optimization to achieve a favorable compromise among several competing design objectives. Computational simulations of fluid dynamics, electromagnetics, and rotordynamics were performed in two stages: first using reduced-order formulations to permit rapid optimization of the key design parameters; followed by rigorous CFD and FEA simulations for calibration, validation, and detailed optimization. Over 20 design configurations were initially considered, leading to three pump topologies, judged on the basis of a multi-component analysis including criteria for anatomic fit, performance, biocompatibility, reliability, and manufacturability. This led to fabrication of a mixed-flow magnetically levitated pump, the PF3, having a displaced volume of 16.6 cc, approximating the size of a AA battery and producing a flow capacity of 0.3-1.5 L/min. Initial in vivo evaluation demonstrated excellent hemocompatibility after 72 days of implantation in an ovine. In summary, combination of prescriptive and heuristic design principles have proven effective in developing a miniature magnetically levitated blood pump with excellent performance and biocompatibility, suitable for integration into chronic circulatory support system for infants and young children; aiming for a clinical trial within 3 years.

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Title: Permanently Blocked Stem Cells Derived from Breast Cancer Cell Lines

Summary: Cancer stem cells (CSCs) are thought to be resistant to standard chemotherapeutic drugs and the inimical conditions of the tumor microenvironment. Obtaining CSCs in sufficient quantities and maintaining their undifferentiated state have been major hurdles to their further characterization and to the identification of new pharmaceuticals that preferentially target these cells. We describe here the tagging of CSC-like populations from four human breast cancer cell lines with green fluorescent protein (GFP) under the control of the Oct3/4 stem cell-specific promoter. As expected, GFP was expressed by the CSC-enriched populations. An unanticipated result, however, was that these cells remained blocked in a CSC-like state and tended to be resistant to chemotherapeutic drugs as well as acidotic and hypoxic conditions. These CSC-like cells possessed several other in vitro attributes of CSCs and were able to reproducibly generate tumors in immunocompromised mice from as few as 100 cells. Moreover, the tumors derived from these cells were comprised almost exclusively of pure CSCs. The ability of the Oct3/4 promoter to block CSC differentiation underscores its potential general utility for obtaining highly purified CSC populations, although the mechanism by which it does so remains undefined and subject to further study. Nonetheless, such stable cell lines should be extremely valuable tools for studying basic questions pertaining to CSC biology and for the initial identification of novel CSC-specific chemotherapeutic agents, which can then be verified in primary CSCs.

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Title: Using Nanoparticle-Filled Microcapsules for Site-Specific Healing of Damaged Substrates: Creating a “Repair-and-Go” System

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Title: Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction

Summary: Tracheal injury is a rare but complex problem. Primary tracheal reconstructions are commonly performed, but complications such as tension and inadequate vascular supply limit the length of surgical resection. The objective of the present study was to determine whether a hydrated, decellularized porcine tracheal extracellular matrix showed the potential to serve as a functional tracheal replacement graft. Porcine tracheas were decellularized and evaluated to characterize their biochemical composition and biomechanical behavior. Hydrated decellularized tracheal matrix (HDTM) grafts (>5 cm) were implanted heterotopically beneath the strap muscle and wrapped in the omentum in a canine model for 2 and 8 weeks followed by histologic and mechanical analysis. HDTM patches (2 x 3 cm) were also used in a patch tracheoplasty model. The repair site was evaluated bronchoscopically and radiographically, and the grafts were analyzed by histologic methods to evaluate epithelialization and persistence of the cartilage rings. The present study showed that HDTM maintains mechanical characteristics necessary for function under physiologic loading conditions even after 8 weeks of heterotopic implantation. After orthotopic implantation, the grafts were shown to support development of a columnar, pseudostratified, ciliated epithelium, but the cartilage structures showed histologic evidence of degradation and limited new cartilage formation. The results of the study showed tracheal ECM scaffolds support the formation of site-specific epithelium and provide sufficient mechanical integrity withstand physiologic pressures in the short-term. However, for long-term success, it appears that pre-implantation to allow vascularization or preseeding of the graft with chondrocytes will be necessary. Copyright 2010 Elsevier Ltd. All rights reserved.

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Title: A biohybrid artificial lung prototype with active mixing of endothelialized microporous hollow fibers

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Title: An Adequately Robust Early TNF-a Response Is a Hallmark of Survival Following Trauma/Hemorrhage

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