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1.  Short Term Interactions with Long Term Consequences: Modulation of Chimeric Vessels by Neural Progenitors 
PLoS ONE  2012;7(12):e53208.
Vessels are a critical and necessary component of most tissues, and there has been substantial research investigating vessel formation and stabilization. Several groups have investigated coculturing endothelial cells with a second cell type to promote formation and stabilization of vessels. Some have noted that long-term vessels derived from implanted cocultures are often chimeric consisting of both host and donor cells. The questions arise as to whether the coculture cell might impact the chimeric nature of the microvessels and can modulate the density of donor cells over time. If long-term engineered microvessels are primarily of host origin, any impairment of the host's angiogenic ability has significant implications for the long-term success of the implant. If one can modulate the host versus donor response, one may be able to overcome a host's angiogenic impairment. Furthermore, if one can modulate the donor contribution, one may be able to engineer microvascular networks to deliver molecules a patient lacks systemically for long times. To investigate the impact of the cocultured cell on the host versus donor contributions of endothelial cells in engineered microvascular networks, we varied the ratio of the neural progenitors to endothelial cells in subcutaneously implanted poly(ethylene glycol)/poly-L-lysine hydrogels. We found that the coculture of neural progenitors with endothelial cells led to the formation of chimeric host-donor vessels, and the ratio of neural progenitors has a significant impact on the long term residence of donor endothelial cells in engineered microvascular networks in vivo even though the neural progenitors are only present transiently in the system. We attribute this to the short term paracrine signaling between the two cell types. This suggests that one can modulate the host versus donor contributions using short-term paracrine signaling which has broad implications for the application of engineered microvascular networks and cellular therapy more broadly.
doi:10.1371/journal.pone.0053208
PMCID: PMC3531360  PMID: 23300890
2.  Nanospheres Delivering the EGFR TKI AG1478 Promote Optic Nerve Regeneration: The Role of Size For Intraocular Drug Delivery 
ACS nano  2011;5(6):4392-4400.
Promoting nerve regeneration involves not only modulating the post-injury microenvironment but also ensuring survival of injured neurons. Sustained delivery of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been shown to promote the survival and regeneration of neurons, but systemic administration is associated with significant side effects. We fabricated poly(lactic-co-glycolic acid) (PLGA) microspheres and nanospheres containing the EGFR TKI 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) for intravitreal administration in a rat optic nerve crush injury model. Upon administration, less backflow from the injection site was observed when injecting nanospheres compared to microspheres. Two weeks after intravitreal delivery, we were able to detect microspheres and nanospheres in the vitreous using coumarin-6 fluorescence, but fewer microspheres were observed compared to the nanospheres. At four weeks only nanospheres could be detected. AG1478 microspheres and nanospheres promoted optic nerve regeneration at two weeks, and at four weeks evidence of regeneration was found only in the nanosphere-injected animals. This observation could be attributed to the ease of administration of the nanospheres versus the microspheres, which in turn led to an increased amount of spheres delivered to the vitreous in the nanosphere group compared to the microsphere group. These data provide evidence for use of PLGA nanospheres to deliver AG1478 intravitreally in a single administration to promote nerve regeneration.
doi:10.1021/nn103146p
PMCID: PMC3136352  PMID: 21619059
optic nerve regeneration; nanospheres; microspheres; PLGA; epidermal growth factor receptor; AG1478
3.  Synthetic Platelets: Nanotechnology to Halt Bleeding 
Science translational medicine  2009;1(11):11ra22.
Blood loss is the major cause of death in both civilian and battlefield traumas. Methods to staunch bleeding include pressure dressings and absorbent materials. For example, Quik-clot effectively halts bleeding by absorbing large quantities of fluid and concentrating platelets to augment clotting, but these treatments are limited to compressible and exposed wounds. An ideal treatment would halt bleeding only at the injury site, be stable at room temperature, be administered easily, and work effectively for internal injuries. We have developed synthetic platelets, based on Arg-Gly-Asp functionalized nanoparticles, that halve bleeding time after intravenous administration in a rat model of major trauma. The effects of these synthetic platelets surpass other treatments including recombinant factor VIIa, which is used clinically for uncontrolled bleeding. Synthetic platelets were cleared within 24 hours at a dose of 20 mg/ml, and no complications were seen out to 7 days after infusion, the longest time point studied. These synthetic platelets may be useful for early intervention in trauma and demonstrate the role that nanotechnology can have in addressing unmet medical needs.
doi:10.1126/scitranslmed.3000397
PMCID: PMC2992987  PMID: 20371456
PLGA; nanoparticles; PEG; hemostasis; coagulation cascade; trauma
4.  Engineering the CNS stem cell microenvironment 
Regenerative medicine  2009;4(6):865-877.
The loss of neural tissue underlies the symptomatology of several neurological insults of disparate etiology, including trauma, cerebrovascular insult and neurodegenerative disease. Restoration of damaged neural tissue through the use of exogenous or endogenous neural stem or progenitor cells is an enticing therapeutic option provided one can control their proliferation, migration and differentiation. Initial attempts at CNS tissue engineering relied on the intrinsic cellular properties of progenitor cells; however, it is now appreciated that the microenvironment surrounding the cells plays an indispensible role in regulating stem cell behavior. This article focuses on attempts to engineer the neural stem cell microenvironment by utilizing the major cellular components of the niche (endothelial cells, astrocytes and ependymal cells) and the extracellular matrix in which they are embedded.
doi:10.2217/rme.09.62
PMCID: PMC2884372  PMID: 19903005
microenvironment; neural progenitor cell; neural stem cell; neural stem cell niche
5.  Engineering angiogenesis following spinal cord injury: A coculture of neural progenitor and endothelial cells in a degradable polymer implant leads to an increase in vessel density and formation of the blood-spinal cord barrier 
Angiogenesis precedes recovery following spinal cord injury (SCI), and its extent correlates with neural regeneration suggesting that angiogenesis may play a role in repair. An important precondition for studying the role of angiogenesis is the ability to induce it in a controlled manner. Previously, we showed that a coculture of endothelial cells (ECs) and neural progenitor cells (NPCs) promoted the formation of stable tubes in vitro and stable, functional vascular networks in vivo in a subcutaneous model. We sought to test whether a similar coculture would lead to formation of stable functional vessels in the spinal cord following injury. We created microvascular networks in a biodegradable two component implant system and tested the ability of the coculture or controls (lesion control, implant alone, implant plus ECs, or implant plus NPCs) to promote angiogenesis in a rat hemisection model of spinal cord injury. The coculture implant led to a four fold increase in functional vessels compared to the lesion control, implant alone, or implant plus NPCs groups and a 2 fold increase in functional vessels over the implant plus ECs group. Furthermore, half of the vessels in the coculture implant exhibited positive staining for the endothelial barrier antigen, a marker for formation of the blood spinal cord barrier (BSB). No other groups showed positive staining for the BSB in the injury epicenter. This work provides a novel method to induce angiogenesis following SCI and a foundation for studying its role in repair.
doi:10.1111/j.1460-9568.2008.06567.x
PMCID: PMC2764251  PMID: 19120441
rat; microvasculature; neural progenitor cells; endothelial cells; hydrogel; scaffold; PLGA; blood-spinal cord barrier
8.  Donald Winnicott 
PMCID: PMC1438904  PMID: 20894373
12.  Prenatal care in Libya 
PMCID: PMC1437136  PMID: 20894305
14.  Advice and Contraception 
British Medical Journal  1970;2(5709):600-601.
PMCID: PMC1700251
16.  Health Visitors 
British Medical Journal  1968;4(5623):122-123.
PMCID: PMC1912126
18.  Organization for Social Paediatrics* 
Archives of Disease in Childhood  1962;37(193):318-320.
PMCID: PMC2012854  PMID: 14007120
19.  Weight in Relation to Pregnancy Toxaemia 
British Medical Journal  1957;2(5057):1338-1340.
PMCID: PMC1963080  PMID: 13479713
21.  Rickets in Singapore 
Archives of Disease in Childhood  1946;21(105):37-51.
Images
PMCID: PMC1987984  PMID: 21032327
22.  Welfare Work 
British Medical Journal  1945;2(4430):786.
PMCID: PMC2060379
23.  Clinical ascariasis in children 
Archives of Disease in Childhood  1938;13(75):235-240.
Images
PMCID: PMC1975573  PMID: 21032110
24.  Whither Welfare? 
British Medical Journal  1941;1(4192):719-721.
PMCID: PMC2161858

Results 1-25 (25)