Nanoghosts: Mesenchymal Stem cells derived nanoparticles as a unique approach for cartilage regeneration.

Osteoarthritis (OA) is a chronic degenerative disease, which affects the joints and is characterized by inflammation, cartilage loss and bone changes. Nowadays, there are no treatments for OA, and current therapies are focused on relieving the symptoms. As a new therapy approach, micro and nanoparticles have been extensively explored and among all the studied particles, the use of cell-membrane-based particles is expanding. Another promising approach studied to treat OA, is the use of mesenchymal stem cells (MSCs) which play an important role modulating inflammation. We developed a novel kind of MSCs' cytoplasmic-membrane-based nanoparticles, termed nano-ghosts (NGs). Retaining MSCs' surface properties and lacking cells' internal machinery allow the NGs to have immunomodulatory capacity and to be immune-evasive while not susceptible to host-induced changes. In this study, we demonstrate NGs' ability to target cartilage tissues, in vitro and in vivo, while modulating the inflammatory process. In vivo studies demonstrated NGs ability to act as an immunomodulatory drug slowing down cartilage degeneration process. Our proof-of-concept experiments show that NGs system is a versatile nano-carrier system, capable of therapeutics loading, with targeting capabilities towards healthy and inflamed cartilage cells. Our results, along with previously published data, clearly reveal the NGs system as a promising nano-carrier platform and as a potential immunomodulatory drug for several inflammation-related diseases.

Evaluation of biomimetic hyaluronic-based hydrogels with enhanced endogenous cell recruitment and cartilage matrix formation.

Biomaterials play a pivotal role in cell-free cartilage repair approaches, where cells must migrate through the scaffold, fill the defect, and then proliferate and differentiate facilitating tissue remodeling. Here we used multiple assays to test the influence of chemokines and growth factors on cell migration and cartilage repair in two different hyaluronan (HA)-based hydrogels. We first investigated bone marrow Mesenchymal Stromal Cells (BMSC) migration in vitro, in response to different concentrations of platelet-derived growth factor-BB (PDGF-BB), chemokine ligand 5 (CCL5/RANTES) and stromal cell-derived factor 1 (SDF-1), using a 3D spheroid-based assay. PDGF-BB was selected as most favourable chemotactic agent, and MSC migration was assessed in the context of physical impediment to cell recruitment by testing Fibrin-HA and HA-Tyramine hydrogels of different cross-linking densities. Supplementation of PDGF-BB stimulated progressive migration of MSC through the gels over time. We then investigated in situ cell migration into the hydrogels with and without PDGF-BB, using a cartilage-bone explant model implanted subcutaneously in athymic mice. In vivo studies show that when placed into an osteochondral defect, both hydrogels supported endogenous cell infiltration and provided an amenable microenvironment for cartilage production. These processes were best supported in Fibrin-HA hydrogel in the absence of PDGF-BB. This study used an advanced preclinical testing platform to select an appropriate microenvironment provided by implanted hydrogels, demonstrating that HA-based hydrogels can promote the initial and critical step of endogenous cell recruitment and circumvent some of the clinical challenges in cartilage tissue repair. STATEMENT OF SIGNIFICANCE: The challenge of articular cartilage repair arises from its complex structure and architecture, which confers the unique mechanical behavior of the extracellular matrix. The aim of our research is to identify biomaterials for implants that can support migration of endogenous stem and progenitor cell populations from cartilage and bone tissue, in order to permanently replace damaged cartilage with the original hyaline structure. Here, we present an in vitro 3D spheroid-based migration assay and an osteochondral defect model, which provide the opportunity to assess biomaterials and biomolecules, and to get stronger experimental evidence of the not well-characterized dynamic process of endogenous cells colonization in an osteochondral defect. Furthermore, the delicate step of early cell migration into biomaterials towards functional tissue engineering is reproduced. These tests can be used for pre-clinical testing of newly developed material designs in the field of scaffold engineering.

Novel PGS/PCL electrospun fiber mats with patterned topographical features for cardiac patch applications.

Nano- and micro-scale topographical features play a critical role in the induction and maintenance of various cellular properties and functions, including morphology, adhesion, gene regulation, and cell-to-cell communication. In addition, recent studies have indicated that the structure and function of heart tissue are also sensitive to mechanical cues at the nano- and micro-scale. Although fabrication methods exist for generating topographical features on polymeric scaffolds for cell culture, current techniques, especially those with nano-scale resolution, are typically complex, prohibitively expensive and not accessible to most biology laboratories. Here, we present a simple and tunable fabrication method for the production of patterned electrospun fibers that simulate the complex anisotropic and multi-scale architecture of cardiac tissue, to promote cardiac cell alignment. This method is based on the combination of electrospinning and soft lithography techniques, in which electrospun fibers, based on a blend of poly(glycerol sebacate) and poly(caprolactone), were collected on a patterned Teflon-coated silicon wafer with imprinted topographical features. Different surface topographies were investigated, such as squares and grooves, with constant or different interspatial distances. In vitro cell culture studies successfully demonstrated the alignment of both C2C12 myoblasts and neonatal rat cardiomyocytes on fabricated electrospun patterned surfaces. C2C12 cells were cultured over a period of 72h to study the effect of topographical cues on cell morphology. Cells attached within the first 8h after seeding and after 24h most of the cells started to align responding to the topographical cues. Similarly, cardiomyocytes responded to the topographical features by aligning themselves and by expressing Connexin 43 along cellular junctions. Summarizing, we have developed a new method with the potential to significantly promote cardiac tissue engineering by fabricating electrospun fibers with defined topographical features to guide and instruct donor and/or host cells.

Dietary salt intake and blood pressure.

With an index for dietary salt use designed to provide a semiquantitative estimate of salt intake, we have found that in a sample representative of the 2.1 million adults in Connecticut, the mean BP of those at the 90th percentile or higher of salt intake differs by a quantitatively insignificant amount from the mean BP of those at the tenth percentile or lower of salt intake. When we examined the obese (body mass index, 90th percentile or higher) separately, similar results were obtained. These findings indicate that it is unlikely dietary salt intake has a clinically significant effect on BP in the majority of individuals in a large defined population, but do not exclude the possibility of a clinically significant effect in a small subgroup of salt-sensitive individuals.

Mortality and cancer incidence experience of employees in a nuclear fuels fabrication plant.

The mortality and cancer incidence experience of 4,106 employees in a nuclear fuels fabrication plant was evaluated in this retrospective cohort study. Standardized mortality (SMR) and incidence ratios were calculated for groups of employees holding different jobs in the company associated with various types of industrial exposures and with low levels of radiation. Connecticut population mortality rates and Connecticut Tumor Registry incidence rates, specific for age-sex, calendar year and cause of death or cancer site, were used for the calculation of expected rates. Results showed the SMR for all male employees to be significantly lower than expected for all causes and what would be expected for all cancer deaths. More deaths were observed than expected from diseases of the central and peripheral nervous system and from obstructive pulmonary disease. The overall cancer incidence experience of the male employees was significantly lower than expected; cancer of the brain was found to be significantly higher than expected among the industrial employees. These was no risk associated with any particular job exposure group. Log linear models analysis showed no significant effect from industrial and radiation exposures or from their combined influence.

The prevalence distribution of hypertension: Connecticut adults 1978-1979.

The results of the first Connecticut Blood Pressure Survey are reported. It was found that sharp differences exist in the prevalence of hypertension by age and sex but that race differences are much less than previously reported for United States populations. Differences were also found between men and women with respect to the patterns of treatment and control. Age differences in treatment and control are noted. The findings reported are based on a statewide probability sample for which the target population exceeded 2 million persons. Because of the complexity of sampling such a population an extensive discussion of the survey method is given.

Crowding in prison: the relationship between changes in housing mode and blood pressure.

The relationship between change in mode of housing and corresponding blood pressure (BP) change was investigated among 568 male prisoners as an analogue to animal studies which have shown that crowding elevates BP. The transfer from single occupancy cells to multiple occupancy dormitories was associated with a statistically significant mean increase in systolic blood pressure (SBP). In contrast, men who remained in single cells had little mean change in SBP over time. Inmates who were retransferred to cells after a short stay in dormitories experienced a mean decline in SBP, which suggests that crowding may be reversible in its early stages. SBP also decreased after continued stay in the dormitories, indicating that adaptation may occur. The implications of these findings for crowding theory and their contribution to an understanding of response to the prison environment are discussed.

Psychophysiological responses to the urban environment.

The relationship of urbanization to bodily changes and chronic disease is examined. Urban stress, as defined principally by one of its components, crowding, is examined in its role in the development of high blood pressure as well as in the modification of behavior and bodily function. Several sources of data are presented including those from animal studies, observations in man and some new data collected by the authors. The concept of information overload, the effects of noise on performance and on chronic disease, the psychophysiological effects of driving in traffic and the behavioral and bodily effects of crowding in man and animals are all presented. This paper intends to give the reader an overview of the complexity of the relationship of urban stress to behavioral changes and chronic disease. This relationship is described, and its multiple components, both in the environment and the nervous system, are enumerated.