Jeffrey Lotz

Publications of Jeffrey Lotz

• Antithrombogenic modification of small-diameter microfibrous vascular grafts.

  Authors: Craig K Hashi, Nikita Derugin, Randall Raphael R Janairo, Randall Lee, David Schultz, Jeffrey Lotz, Song Li

  Arteriosclerosis, thrombosis, and vascular biology. 05/2010; 30(8):1621-7.

  To develop small-diameter vascular grafts with a microstructure similar to native matrix fibers and with chemically modified microfibers to prevent thrombosis. Microfibrous vascular grafts (1-mmTo develop small-diameter vascular grafts with a microstructure similar to native matrix fibers and with chemically modified microfibers to prevent thrombosis. Microfibrous vascular grafts (1-mm internal diameter) were fabricated by electrospinning, and hirudin was conjugated to the poly (L-lactic acid) microfibers through an intermediate linker of poly(ethylene glycol). The modified microfibrous vascular grafts were able to reduce platelet adhesion/aggregation onto microfibrous scaffolds, and immobilized hirudin suppressed thrombin activity that may interact with the scaffolds. This 2-pronged approach to modify microfibrous vascular graft showed significantly improved patency (from 50% to 83%) and facilitated endothelialization, and the microfibrous structure of the vascular grafts allowed efficient graft remodeling and integration, with the improvement of mechanical property (elastic modulus) from 3.5 to 11.1 MPa after 6 months of implantation. Microfibrous vascular grafts with antithrombogenic microfibers can be used as small-diameter grafts, with excellent patency and remodeling capability.

• New Challenges for Intervertebral Disc Treatment using Regenerative Medicine.

  Authors: Koichi Masuda, Jeffrey Lotz

  Tissue engineering. Part B, Reviews. 11/2009;

  The development of tissue engineering therapies for the intervertebral disc is challenging due to ambiguities of disease and pain mechanisms in patients, and lack of consensus on pre-clinical modelsThe development of tissue engineering therapies for the intervertebral disc is challenging due to ambiguities of disease and pain mechanisms in patients, and lack of consensus on pre-clinical models for safety and efficacy testing. While the issues associated with model selection for studying orthopaedic diseases or treatments has been discussed often, the multi-faceted challenges associated with developing intervertebral disc tissue engineering therapies requires special discussion. This review covers topics relevant to the clinical translation of tissue-engineered technologies: 1) the unmet clinical need; 2) appropriate models for safety and efficacy testing; 3) the need for standardized model systems; and 4) the translational pathways leading to a clinical trial. For pre-clinical evaluation of new therapies, we recommend establishing biologic plausibility of efficacy and safety using models of increasing complexity, starting with cell culture, small animals (rats and rabbits), then large animals (goat and mini-pig) that more closely mimic nutritional, biomechanical, and surgical realities of human application. The use of standardized and reproducible experimental procedures and outcome measures is critical for judging relative efficacy. Finally, success will hinge on carefully designed clinical trials with well-defined patient selection criteria, gold-standard controls, and objective outcome metrics to assess performance in the early post-operative period.

• The influence of ferucarbotran on the chondrogenesis of human mesenchymal stem cells.

  Authors: Tobias D Henning, Elizabeth J Sutton, Anne Kim, Daniel Golovko, Andrew Horvai, Larry Ackerman, Barbara Sennino, Donald McDonald, Jeffrey Lotz, Heike E Daldrup-Link

  Contrast media & molecular imaging. 09/2009;

  For in vivo applications of magnetically labeled stem cells, biological effects of the labeling procedure have to be precluded. This study evaluates the effect of different ferucarbotran cellFor in vivo applications of magnetically labeled stem cells, biological effects of the labeling procedure have to be precluded. This study evaluates the effect of different ferucarbotran cell labeling protocols on chondrogenic differentiation of human mesenchymal stem cells (hMSC) as well as their implications for MR imaging. hMSC were labeled with ferucarbotran using various protocols: cells were labeled with 100 microg Fe/ml for 4 and 18 h and additional samples were cultured for 6 or 12 days after the 18 h labeling. Supplementary samples were labeled by transfection with protamine sulfate. Iron uptake was quantified by ICP-spectrometry and labeled cells were investigated by transmission electron microscopy and by immunostaining for ferucarbotran. The differentiation potential of labeled cells was compared with unlabeled controls by staining with Alcian blue and Hematoxylin and Eosin, then quantified by measurements of glucosaminoglycans (GAG). Contrast agent effect at 3 T was investigated on days 1 and 14 of chondrogenic differentiation by measuring signal-to-noise ratios on T(2)-SE and T(2)*-GE sequences. Iron uptake was significant for all labeling protocols (p < 0.05). The uptake was highest after transfection with protamine sulfate (25.65 +/- 3.96 pg/cell) and lowest at an incubation time of 4 h without transfection (3.21 +/- 0.21 pg/cell). While chondrogenic differentiation was decreased using all labeling protocols, the decrease in GAG synthesis was not significant after labeling for 4 h without transfection. After labeling by simple incubation, chondrogenesis was found to be dose-dependent. MR imaging showed markedly lower SNR values of all labeled cells compared with the unlabeled controls. This contrast agent effect persisted for 14 days and the duration of differentiation. Magnetic labeling of hMSC with ferucarbotran inhibits chondrogenesis in a dose-dependent manner when using simple incubation techniques. When decreasing the incubation time to 4 h, inhibition of chondrogenesis was not significant. Copyright (c) 2009 John Wiley & Sons, Ltd.

• The tissue diagnostic instrument.

  Authors: Paul Hansma, Hongmei Yu, David Schultz, Azucena Rodriguez, Eugene A Yurtsev, Jessica Orr, Simon Tang, Jon Miller, Joseph Wallace, Frank Zok [......] Carol Chen, Mathilde Peters, David Kohn, Jenni Buckley, Xiaojuan Li, Lisa Pruitt, Adolfo Diez-Perez, Tamara Alliston, Valerie Weaver, Jeffrey Lotz

  The Review of scientific instruments. 06/2009; 80(5):054303.

  Tissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral diskTissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral disk degeneration, cancer, atherosclerosis, osteoarthritis, osteoporosis, and tooth decay. Here we introduce the tissue diagnostic instrument (TDI), a device designed to probe the mechanical properties of normal and diseased soft and hard tissues not only in the laboratory but also in patients. The TDI can distinguish between the nucleus and the annulus of spinal disks, between young and degenerated cartilage, and between normal and cancerous mammary glands. It can quantify the elastic modulus and hardness of the wet dentin left in a cavity after excavation. It can perform an indentation test of bone tissue, quantifying the indentation depth increase and other mechanical parameters. With local anesthesia and disposable, sterile, probe assemblies, there has been neither pain nor complications in tests on patients. We anticipate that this unique device will facilitate research on many tissue systems in living organisms, including plants, leading to new insights into disease mechanisms and methods for their early detection.

• Pressure and Distortion Regulate Human Mesenchymal Stem Cell Gene Expression.

  Authors: Anne Haudenschild, Adam Hsieh, Sunil Kapila, Jeffrey Lotz

  Annals of biomedical engineering. 02/2009;

  While the concept that physical forces such as tension and compression are involved in mature tissue modeling is widely accepted, the role of these specific types of mechanical loading in theWhile the concept that physical forces such as tension and compression are involved in mature tissue modeling is widely accepted, the role of these specific types of mechanical loading in the differentiation and maturation of uncommitted cell types like human mesenchymal stem cells (hMSCs) is currently unknown. We observed that hMSCs have the fundamental ability to distinguish between dynamic tensile and compressive loading by regulating distinct gene expression patterns and that these differences in gene expression can be related to conformational changes in cell shape and volume. Dynamic tension was found to regulate both fibroblastic and osteogenic associated genes while dynamic compression up-regulated genes associated with chondrogenesis. Identifying genes involved in the mechanotransduction of different modes of physical loading in hMSC may greatly enhance the ability to rationally design tissue regeneration systems to restore proper tissue function.

• Multiple Differentiation Capacity of STRO-1+/CD146+ PDL Mesenchymal Progenitor Cells.

  Authors: Jinping Xu, Wei Wang, Yvonne Kapila, Jeffrey Lotz, Sunil Kapila

  Stem cells and development. 08/2008;

  Although mesenchymal progenitor cells can be isolated from periodontal ligament (PDL) tissues using stem cell markers STRO-1 and CD146, the proportion of these cells that have the capacity toAlthough mesenchymal progenitor cells can be isolated from periodontal ligament (PDL) tissues using stem cell markers STRO-1 and CD146, the proportion of these cells that have the capacity to differentiate into multiple cell lineages remains to be determined. This study was designed to quantify the proportions of primary human PDL cells that can undergo multi-lineage differentiation, and to compare the magnitude of these capabilities relative to bone marrow-derived mesenchymal stem cells (MSC) and parental PDL (PPDL) cells. PDL mesenchymal progenitor (PMP) cells were isolated from PPDL cells using the markers STRO-1 and CD146. The colony-forming efficiency and multi-lineage differentiation potential of PMP, PPDL, and MSCs under chondrogenic, osteogenic and adipogenic conditions were determined. Flow cytometry revealed that on average 2.6% of PPDL cells were STRO-1+/CD146+, whereas more than 63% were STRO-1-/CD146-. Colony-forming efficiency of STRO-1+/CD146+ PMP cells (19.3%) and MSCs (16.7%) was significantly higher than that of PPDL cells (6.8%). Cartilage specific genes, early markers of osteoblastic differentiation, and adipogenic markers were significantly up-regulated under appropriate conditions in PMP cells and MSCs compared to either their non-induced counterparts or induced PPDL cells. Consistent with these findings, immunohistochemistry revealed substantial accumulation of cartilaginous macromolecules, mineralized calcium nodules, and lipid vacuoles under chondrogenic, osteogenic or adipogenic conditions in PMP and MSC cultures, respectively, compared to non-induced controls or induced PPDL cells. Thus, STRO-1+/CD146+ PMP cells demonstrate multi-lineage differentiation capacity comparable in magnitude to MSCs, and could potentially be utilized for regeneration of the periodontium and other tissues.

• The potential role of mesenchymal stem cell therapy for intervertebral disc degeneration: a critical overview.

  Authors: Frank L Acosta, Jeffrey Lotz, Christopher P Ames

  Neurosurgical focus. 10/2005; 19(3):E4.

  Low-back pain is the most common health problem for men and women between 20 and 50 years of age, resulting in 13 million doctor visits in the US annually, with significant costs to society in termsLow-back pain is the most common health problem for men and women between 20 and 50 years of age, resulting in 13 million doctor visits in the US annually, with significant costs to society in terms of lost time from work and direct and indirect medical expenses. Although the exact origin of most cases of low-back pain remains unknown, it is understood that degenerative damage to the intervertebral disc (IVD) plays a central role in the pathogenic mechanism leading to this disorder. Current treatment modalities for disc-related back pain (selective nerve root blocks, surgical discectomy and fusion) are costly procedures aimed only at alleviating symptoms. Consequently, there is growing interest in the development of novel technologies to repair or regenerate the degenerated IVD. Recently, mesenchymal stem cells (MSCs) have been found to possess the capacity to differentiate into nucleus pulposus-like cells capable of synthesizing a physiological, proteoglycan-rich extracellular matrix characteristic of healthy IVDs. In this article, the authors review the use of MSCs for repopulation of the degenerating IVD. Although important obstacles to the survival and proliferation of stem cells within the degenerating disc need to be overcome, the potential for MSC therapy to slow or reverse the degenerative process remains substantial.

• Effects of controlled dynamic disc distraction on degenerated intervertebral discs: an in vivo study on the rabbit lumbar spine model.

  Authors: Markus Kroeber, Frank Unglaub, Thorsten Guehring, Thorsten Guegring, Andreas Nerlich, Tamer Hadi, Jeffrey Lotz, Claus Carstens

  Spine. 02/2005; 30(2):181-7.

  STUDY DESIGN: An in vivo study on the rabbit lumbar spine model. OBJECTIVES: Effects of temporary dynamic distraction on intervertebral discs were studied on the lumbar spine rabbit model toSTUDY DESIGN: An in vivo study on the rabbit lumbar spine model. OBJECTIVES: Effects of temporary dynamic distraction on intervertebral discs were studied on the lumbar spine rabbit model to characterize the changes associated with disc distraction and to evaluate feasibility of temporary disc distraction to previously compressed discs in order to stimulate disc regeneration. SUMMARY OF BACKGROUND DATA: Studies have shown that accelerated degeneration of the intervertebral disc results from altered mechanical loading conditions. The development of methods for the prevention of disc degeneration and the restoration of disc tissue that has already degenerated are needed. METHODS: New Zealand white rabbits (n = 32) were used for this study. The rabbits were randomly assigned to one of five groups. In 12 animals, the discs were first loaded for 28 days using a custom-made external loading device to stimulate disc degeneration. After 28 days loading time, the discs in six animals were distracted for 7 days and in six animals for 28 days using the same external device, however, modified as dynamic distraction device. In six animals, the discs were distracted for 28 days without previous loading; and in six animals, the discs were loaded for 28 days and afterwards the loading device removed for 28 days for recovery without distraction. Six animals were sham operated. The external device was situated; however, the discs remained undistracted and they also served as controls. After 28 to 56 days loading and distraction time, the animals were killed and the lumbar spine was harvested for examination. Disc height, disc morphology, cell viability, relative neutral zone, and tangent modulus were measured. RESULTS: After 28 days of loading, the discs demonstrated a significant decrease in disc space. Histologically, disorganization of the architecture of the anulus occurred. The number of dead cells increased significantly in the anulus and cartilage endplate. These changes were reversible after 28 days of distraction. The disc thickness increased significantly as compared with the specimens from the 28 days loading group without distraction. Histologically, the discs showed signs of tissue regeneration after 28 days of distraction. The number of dead cells decreased significantly in comparison with the loaded discs without distraction. The flexibility of compressed discs was higher than of compressed/distracted discs. CONCLUSIONS: The results of this study suggest that disc regeneration can be induced by axial dynamic distraction in the rabbit intervertebral disc. The decompressed rabbit intervertebral discs showed signs of tissue recovery on a biologic, cellular, and a biomechanical level after 28 days of distraction.

• Diffraction enhanced imaging of articular cartilage and comparison with micro-computed tomography of the underlying bone structure.

  Authors: Sharmila Majumdar, Ahi Sema Issever, Andrew Burghardt, Jeffrey Lotz, Fulvia Arfelli, Luigi Rigon, Gabriele Heitner, Ralf Hendrik Menk

  European radiology. 09/2004; 14(8):1440-8.

  The goal of this study was to explore the role of diffraction enhanced X-ray imaging (DEI) for assessing changes in osteoarthritic cartilage and correlating the findings with concurrent changes inThe goal of this study was to explore the role of diffraction enhanced X-ray imaging (DEI) for assessing changes in osteoarthritic cartilage and correlating the findings with concurrent changes in the underlying bone imaged using micro-computed tomography (microCT). DEI was used to image femoral head specimens at various beam energies. DEI utilizes a monochromatic, highly collimated beam, with an analyzer crystal that selectively weights out photons according to the angle they have been deviated with respect to the original direction. This provides images of very high contrast, with the rejection of X-ray scatter. The underlying bone was imaged using microCT and measures quantifying the bone structure were derived. Confirmation of cartilage degeneration was obtained from histology and polarized light microscopy. DEI allowed the visualization of articular cartilage and reflected the fibrillations and fissures in tissues from degenerated joints. The trabecular bone underlying the most degenerated articular cartilage showed increased bone volume fraction and more plate-like characteristics, compared with that underlying normal appearing cartilage. The histology and polarized light microscopy images reflected the DEI based features of cartilage architecture. These data reflect the ability of X-ray based emerging technologies to depict cartilage-bone interactions in joint degeneration.

• Diffraction enhanced imaging of articular cartilage and comparison with micro-computed tomography of the underlying bone structure

  Authors: Sharmila Majumdar, Ahi Sema Issever, Andrew Burghardt, Jeffrey Lotz, Fulvia Arfelli, Luigi Rigon, Gabriele Heitner, Ralf-Hendrik Menk

  European radiology. 14(8):1440-8.

  The goal of this study was to explore the role of diffraction enhanced X-ray imaging (DEI) for assessing changes in osteoarthritic cartilage and correlating the findings with concurrent changes inThe goal of this study was to explore the role of diffraction enhanced X-ray imaging (DEI) for assessing changes in osteoarthritic cartilage and correlating the findings with concurrent changes in the underlying bone imaged using micro-computed tomography (microCT). DEI was used to image femoral head specimens at various beam energies. DEI utilizes a monochromatic, highly collimated beam, with an analyzer crystal that selectively weights out photons according to the angle they have been deviated with respect to the original direction. This provides images of very high contrast, with the rejection of X-ray scatter. The underlying bone was imaged using microCT and measures quantifying the bone structure were derived. Confirmation of cartilage degeneration was obtained from histology and polarized light microscopy. DEI allowed the visualization of articular cartilage and reflected the fibrillations and fissures in tissues from degenerated joints. The trabecular bone underlying the most degenerated articular cartilage showed increased bone volume fraction and more plate-like characteristics, compared with that underlying normal appearing cartilage. The histology and polarized light microscopy images reflected the DEI based features of cartilage architecture. These data reflect the ability of X-ray based emerging technologies to depict cartilage-bone interactions in joint degeneration.

• Diffraction enhanced imaging of articular cartilage and comparison with micro-computed tomography of the underlying bone structure.

  Authors: Sharmila Majumdar, Ahi Sema Issever, Andrew Burghardt, Jeffrey Lotz, Fulvia Arfelli, Luigi Rigon, Gabriele Heitner, Ralf-Hendrik Menk

  14(8):1440-1448.

  The goal of this study was to explore the role of diffraction enhanced X-ray imaging (DEI) for assessing changes in osteoarthritic cartilage and correlating the findings with concurrent changes inThe goal of this study was to explore the role of diffraction enhanced X-ray imaging (DEI) for assessing changes in osteoarthritic cartilage and correlating the findings with concurrent changes in the underlying bone imaged using micro-computed tomography (microCT). DEI was used to image femoral head specimens at various beam energies. DEI utilizes a monochromatic, highly collimated beam, with an analyzer crystal that selectively weights out photons according to the angle they have been deviated with respect to the original direction. This provides images of very high contrast, with the rejection of X-ray scatter. The underlying bone was imaged using microCT and measures quantifying the bone structure were derived. Confirmation of cartilage degeneration was obtained from histology and polarized light microscopy. DEI allowed the visualization of articular cartilage and reflected the fibrillations and fissures in tissues from degenerated joints. The trabecular bone underlying the most degenerated articular cartilage showed increased bone volume fraction and more plate-like characteristics, compared with that underlying normal appearing cartilage. The histology and polarized light microscopy images reflected the DEI based features of cartilage architecture. These data reflect the ability of X-ray based emerging technologies to depict cartilage-bone interactions in joint degeneration.

• Quantitative analysis of structural disorder in intervertebral disks using second harmonic generation imaging: comparison with morphometric analysis.

  Authors: Karen M Reiser, Clayton Bratton, Diego R Yankelevich, André Knoesen, Israel Rocha-Mendoza, Jeffrey Lotz

  Journal of biomedical optics. 12(6):064019.

  A novel signal processing algorithm for quantifying structural disorder in biological tissue using second harmonic generation (SHG) imaging is described. Both the magnitude and the pattern ofA novel signal processing algorithm for quantifying structural disorder in biological tissue using second harmonic generation (SHG) imaging is described. Both the magnitude and the pattern of disorder in collagenous tissues can be determined with this method. Mathematical models are used to determine the range of disordered states over which the algorithm can be used, because highly disordered biological samples do not generate second harmonic signals. The method is validated by measuring disorder in heated fascicles using SHG and showing that results are significantly correlated with morphometric determination. Applicability of the method to tissue pathology is demonstrated by analysis of a mouse model of intervertebral disk injury. Disks were subjected to tensile or compressive forces in vivo for one week. Structural disorder in the annulus fibrosus was measured by SHG scanning and by standard morphometric analysis. Values for disorder obtained by SHG scanning were significantly correlated with values obtained by morphometry (p<0.001). Quantitation of disorder using SHG offers significant advantages over morphometric determination. Data obtained in this study suggest that this method can be used to discriminate between reversible and irreversible tissue damage.