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1.  Hydrogels Derived from Central Nervous System Extracellular Matrix 
Biomaterials  2012;34(4):1033-1040.
Biologic scaffolds composed of extracellular matrix (ECM) are commonly used repair devices in preclinical and clinical settings; however the use of these scaffolds for peripheral and central nervous system (CNS) repair has been limited. Biologic scaffolds developed from brain and spinal cord tissue have recently been described, yet the conformation of the harvested ECM limits therapeutic utility. An injectable CNS-ECM derived hydrogel capable of in vivo polymerization and conformation to irregular lesion geometries may aid in tissue reconstruction efforts following complex neurologic trauma. The objectives of the present study were to develop hydrogel forms of brain and spinal cord ECM and compare the resulting biochemical composition, mechanical properties, and neurotrophic potential of a brain derived cell line to a non-CNS-ECM hydrogel, urinary bladder matrix. Results showed distinct differences between compositions of brain ECM, spinal cord ECM, and urinary bladder matrix. The rheologic modulus of spinal cord ECM hydrogel was greater than that of brain ECM and urinary bladder matrix. All ECMs increased the number of cells expressing neurites, but only brain ECM increased neurite length, suggesting a possible tissue-specific effect. All hydrogels promoted three-dimensional uni- or bi-polar neurite outgrowth following 7 days in culture. These results suggest that CNS-ECM hydrogels may provide supportive scaffolding to promote in vivo axonal repair.
PMCID: PMC3512573  PMID: 23158935
2.  A Murine Model of Volumetric Muscle Loss and a Regenerative Medicine Approach for Tissue Replacement 
Tissue Engineering. Part A  2012;18(19-20):1941-1948.
Volumetric muscle loss (VML) resulting from traumatic accidents, tumor ablation, or degenerative disease is associated with limited treatment options and high morbidity. The lack of a reliable and reproducible animal model of VML has hindered the development of effective therapeutic strategies. The present study describes a critical-sized excisional defect within the mouse quadriceps muscle that results in an irrecoverable volumetric defect. This model of VML was used to evaluate the efficacy of a surgically placed inductive biologic scaffold material composed of porcine small intestinal submucosa–extracellular matrix (SIS-ECM). The targeted placement of an SIS-ECM scaffold within the defect was associated with constructive tissue remodeling including the formation of site-appropriate skeletal muscle tissue. The present study provides a reproducible animal model with which to study VML and shows the therapeutic potential of a bioscaffold-based regenerative medicine approach to VML.
PMCID: PMC3463275  PMID: 22906411
3.  Partial Characterization of the Sox2+ Cell Population in an Adult Murine Model of Digit Amputation 
Tissue Engineering. Part A  2012;18(13-14):1454-1463.
Tissue regeneration in response to injury in adult mammals is generally limited to select tissues. Nonmammalian species such as newts and axolotls undergo regeneration of complex tissues such as limbs and digits via recruitment and accumulation of local and circulating multipotent progenitors preprogrammed to recapitulate the missing tissue. Directed recruitment and activation of progenitor cells at a site of injury in adult mammals may alter the default wound-healing response from scar tissue toward regeneration. Bioactive molecules derived from proteolytic degradation of extracellular matrix (ECM) proteins have been shown to recruit a variety of progenitor cells in vitro and in vivo to the site of injury. The present study further characterized the population of cells accumulating at the site of injury after treatment with ECM degradation products in a well-established model of murine digit amputation. After a mid-second phalanx digit amputation in 6–8-week-old adult mice, treatment with ECM degradation products resulted in the accumulation of a heterogeneous population of cells, a subset of which expressed the transcription factor Sox2, a marker of pluripotent and adult progenitor cells. Sox2+ cells were localized lateral to the amputated P2 bone and coexpressed progenitor cell markers CD90 and Sca1. Transgenic Sox2 eGFP/+ and bone marrow chimeric mice showed that the bone marrow and blood circulation did not contribute to the Sox2+ cell population. The present study showed that, in addition to circulating progenitor cells, resident tissue-derived cells also populate at the site of injury after treatment with ECM degradation products. Although future work is necessary to determine the contribution of Sox2+ cells to functional tissue at the site of injury, recruitment and/or activation of local tissue-derived cells may be a viable approach to tissue engineering of more complex tissues in adult mammals.
PMCID: PMC3397117  PMID: 22530556
4.  An Isolated Cryptic Peptide Influences Osteogenesis and Bone Remodeling in an Adult Mammalian Model of Digit Amputation 
Tissue Engineering. Part A  2011;17(23-24):3033-3044.
Biologic scaffolds composed of extracellular matrix (ECM) have been used successfully in preclinical models and humans for constructive remodeling of functional, site-appropriate tissue after injury. The mechanisms underlying ECM-mediated constructive remodeling are not completely understood, but scaffold degradation and site-directed recruitment of progenitor cells are thought to play critical roles. Previous studies have identified a cryptic peptide derived from the C-terminal telopeptide of collagen IIIα that has chemotactic activity for progenitor cells. The present study characterized the osteogenic activity of the same peptide in vitro and in vivo in an adult murine model of digit amputation. The present study showed that the cryptic peptide increased calcium deposition, alkaline phosphatase activity, and osteogenic gene expression in human perivascular stem cells in vitro. Treatment with the cryptic peptide in a murine model of mid-second phalanx digit amputation led to the formation of a bone nodule at the site of amputation. In addition to potential therapeutic implications for the treatment of bone injuries and facilitation of reconstructive surgical procedures, cryptic peptides with the ability to alter stem cell recruitment and differentiation at a site of injury may serve as powerful new tools for influencing stem cell fate in the local injury microenvironment.
PMCID: PMC3226059  PMID: 21740273
5.  Recruitment of Progenitor Cells by an Extracellular Matrix Cryptic Peptide in a Mouse Model of Digit Amputation 
Tissue Engineering. Part A  2011;17(19-20):2435-2443.
Biologic scaffolds composed of extracellular matrix (ECM) have been used successfully in preclinical models and humans for constructive remodeling of functional, site-appropriate tissue after injury. The mechanisms underlying ECM-mediated constructive remodeling are not completely understood, but scaffold degradation and site-directed recruitment of both differentiated and progenitor cells are thought to play critical roles. Previous studies have shown that degradation products of ECM scaffolds can recruit a population of progenitor cells both in vitro and in vivo. The present study identified a single cryptic peptide derived from the α subunit of the collagen III molecule that is chemotactic for a well-characterized perivascular stem cell in vitro and causes the site-directed accumulation of progenitor cells in vivo. The oligopeptide was additionally chemotactic for human cortical neural stem cells, rat adipocyte stem cells, C2C12 myoblast cells, and rat Schwann cells in vitro. In an adult murine model of digit amputation, treatment with this peptide after mid-second phalanx amputation resulted in a greater number of Sox2+ and Sca1+,Lin− cells at the site of injury compared to controls. Since progenitor cell activation and recruitment are key prerequisites for epimorphic regeneration in adult mammalian tissues, endogenous site-directed recruitment of such cells has the potential to alter the default wound healing response from scar tissue toward regeneration.
PMCID: PMC3179613  PMID: 21563860
6.  Mitochondria-mediated hormetic response in life span extension of calorie-restricted Saccharomyces cerevisiae 
Age  2010;33(2):143-154.
Calorie restriction (CR) is the only proven regimen, which confers lifespan extension benefits across the various phyla right from unicellular organisms like yeast to primates. In a bid to elucidate the mechanism of calorie-restriction-mediated life span extension, the role of mitochondria in the process was investigated. In this study, we found that the mitochondrial content in CR cells remains unaltered as compared to cells grown on nonrestricted media. However, mitochondria isolated from CR cells showed increased respiration and elevated reactive oxygen species levels without augmenting adenosine triphosphate (ATP) generation. The antioxidant defense system was amplified in CR mitochondria, and in CR cells a cross protection to hydrogen-peroxide-induced stress was also observed. Moreover, we also documented that a functional electron transport chain was vital for the life span extension benefits of calorie restriction. Altogether, our results indicate that calorie restriction elicits mitohormetic effect, which ultimately leads to longevity benefit.
PMCID: PMC3127463  PMID: 20640543
Calorie restriction; Mitochondria; ROS; Stress resistance; Hormesis; atp2
7.  Evidence of Innervation following Extracellular Matrix Scaffold Mediated Remodeling of Muscular Tissues 
Naturally occurring porcine derived extracellular matrix (ECM) has successfully been used as a biologic scaffold material for site-specific reconstruction of a wide variety of tissues. The site-specific remodeling process includes rapid degradation of the scaffold with concomitant recruitment of mononuclear cells, endothelial cells, and bone marrow derived cells, and can lead to formation of functional skeletal and smooth muscle tissue. However, the temporal and spatial patterns of innervation of the remodeling scaffold material in muscular tissues are not well understood. A retrospective study was conducted to investigate the presence of nervous tissue in a rat model of abdominal wall reconstruction and a canine model of esophageal reconstruction in which ECM scaffolds were used as inductive scaffolds. Evidence of mature nerve, immature nerve, and Schwann cells was found within the remodeled ECM at 28 days in the rat body wall model, and at 91 days post surgery in a canine model of esophageal repair. Additionally, a microscopic and morphologic study that investigated the response of primary cultured neurons seeded upon an ECM scaffold showed that neuronal survival and outgrowth was supported by the ECM substrate. Finally, matricryptic peptides resulting from rapid degradation of the ECM scaffold induced migration of terminal Schwann cells in a concentration dependent fashion in vitro. The findings of this study suggest that the reconstruction of tissues in which innervation is an important functional component is possible with use of biologic scaffolds composed of extracellular matrix.
PMCID: PMC2787980  PMID: 19701935
8.  A Parallel Tracking Method for Acoustic Radiation Force Impulse Imaging 
Radiation force-based techniques have been developed by several groups for imaging the mechanical properties of tissue. Acoustic Radiation Force Impulse (ARFI) imaging is one such method that uses commercially available scanners to generate localized radiation forces in tissue. The response of the tissue to the radiation force is determined using conventional B-mode imaging pulses to track micron-scale displacements in tissue. Current research in ARFI imaging is focused on producing real-time images of tissue displacements and related mechanical properties. Obstacles to producing a real-time ARFI imaging modality include data acquisition, processing power, data transfer rates, heating of the transducer, and patient safety concerns. We propose a parallel receive beamforming technique to reduce transducer heating and patient acoustic exposure, and to facilitate data acquisition for real-time ARFI imaging. Custom beam sequencing was used with a Siemens SONOLINE AntaresTM scanner to track tissue displacements with parallel-receive beam-forming in tissue-mimicking phantoms. Using simulations, the effects of material properties on parallel tracking are observed. Transducer and tissue heating for parallel tracking are compared to standard ARFI beam sequencing. The effects of tracking beam position and size of the tracked region are also discussed in relation to the size and temporal response of the region of applied force, and the impact on ARFI image contrast and signal-to-noise ratio are quantified.
PMCID: PMC1810393  PMID: 17328327

Results 1-8 (8)