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Dukhin S.S.,Novaflux Technologies, Inc. | Labib M.E.,Novaflux Technologies, Inc.
Colloids and Surfaces A: Physicochemical and Engineering Aspects | Year: 2012

Combining the approach of colloid transport with the generalized Higuchi theory of drug release and with the concept of minimum inhibitory concentration (MIC) known in microbiology, the theory of effective drug release from implants has been developed. Effective release of an antibiotic at a concentration above MIC is a necessary condition to achieve protection against infection from implants such as central catheters. The Higuchi theory in its present form is not predictive of the therapeutic effect from medical implants. The theory of effective release presented in this paper specifies two release modes, namely: one with therapeutic usefulness (effective release) and another without therapeutic effect. Therapeutic usefulness may be achieved when the antibiotic concentration, C ti, on the implant surface kills the organisms of interest and prevents the formation and propagation of biofilm when C ti exceeds the corresponding MIC of the released antibiotic compound. Currently, neither the Higuchi theory nor any other theory can provide such prediction. The present approach requires quantification of the antibiotic transport from the drug-polymer blend implant surface into the tissue and accounts for its coupling with drug diffusion inside the blend, a task that has not been developed in existing theories. Our solution to this task resulted in the derivation of an equation for the time of duration of effective release, T e, which depends on MIC, the Higuchi invariant and the characteristics of convective diffusion within the tissue. The latter characteristics include: diffusivity D ti and diffusion layer thickness δ which is controlled by the velocity of the interstitial fluid in tissue. A smaller D ti is favorable because transport from the catheter surface is weaker, while a thinner diffusion layer is harmful because this transport is stronger. The influence of the tangential component of interstitial velocity in the tissue is especially harmful because the diffusion within the incision exit site (IES) will be extremely enhanced such that it may decrease C ti to zero. The incorporation of convective diffusion into the theory of antibacterial protection by means of antibiotic release has revealed that physicochemical mechanisms predict the effectiveness of antibiotic-loaded catheters and defines the conditions necessary to achieve better protection by means of combining the level of catheter loading with antibiotics and the use of wound (IES) dressing. © 2012 Elsevier B.V.


Labib M.E.,Novaflux Technologies, Inc. | Dukhin S.,Novaflux Technologies, Inc. | Murawski J.,Novaflux Technologies, Inc. | Tabani Y.,Novaflux Technologies, Inc. | Lai R.,Novaflux Technologies, Inc.
Advances in Colloid and Interface Science | Year: 2011

During our investigations of two-phase flow in long hydrophobic minitubes and capillaries, we have observed transformation of the main rivulet into different new hydrodynamic modes with the use of different kinds of surfactants. The destabilization of rivulet flow at air velocities < 80 m/s occurs primarily due to the strong branching off of sub-rivulets from the main rivulet during the downstream flow in the tube. The addition of some surfactants of not-so-high surface activity was found to increase the frequency of sub-rivulet formation and to suppress the Rayleigh and sinuous instabilities of the formed sub-rivulets. Such instabilities result in subsequent fragmentation of the sub-rivulets and in the formation of linear or sinuous arrays of sub-rivulet fragments (SRFs), which later transform into random arrays of SRFs. In the downstream flow, SRFs further transform into large sliding cornered droplets and linear droplet arrays (LDAs), a phenomenon which agrees with recent theories. At higher surface activity, suppression of the Rayleigh instability of sub-rivulets with surfactants becomes significant, which prevents sub-rivulet fragmentation, and only the rivulet and sub-rivulets can be visualized in the tube. At the highest surface activity, the bottom rivulet transforms rapidly into an annular liquid film. The surfactant influence on the behavior of the rivulets in minitubes is incomparably stronger than the classic example of the known surfactant stabilizing influence on a free jet. The evolution of a rivulet in the downstream flow inside a long minitube includes the following sequence of hydrodynamic modes/patterns: i) single rivulet; ii) rivulet and sub-rivulets; and iii) rivulet, sub-rivulets, sub-rivulet fragments, cornered droplets, linear droplet arrays, linear arrays of sub-rivulet fragments and annular film. The formation of these many different hydrodynamic patterns downstream is in drastic contrast with the known characteristics of two-phase flow, which demonstrates one mode for the entire tube length. Recent achievements in fluid mechanics regarding the stability of sliding thin films and in wetting dynamics have allowed us to interpret many of our findings. However, the most important phenomenon of the surfactant influence on sub-rivulet formation remains poorly understood. To achieve further progress in this new area, an interdisciplinary approach based on the use of methods of two-phase flow, wetting dynamics and interfacial rheology will be necessary. © 2011 Elsevier B.V.


Dukhin S.S.,New Jersey Institute of Technology | Dukhin S.S.,Novaflux Technologies, Inc. | Labib M.E.,Novaflux Technologies, Inc.
Advances in Colloid and Interface Science | Year: 2013

Drug delivery using nanoparticles as drug carriers has recently attracted the attention of many investigators. Targeted delivery of nanoparticles to the lymph nodes is especially important to prevent cancer metastasis or infection, and to diagnose disease stage. However, systemic injection of nanoparticles often results in organ toxicity because they reach and accumulate in all the lymph nodes in the body. An attractive strategy would be to deliver the drug-loaded nanoparticles to a subset of draining lymph nodes corresponding to a specific site or organ to minimize systemic toxicity. In this respect, mucosal delivery of nanoparticles to regional draining lymph nodes of a selected site creates a new opportunity to accomplish this task with minimal toxicity. One example is the delivery of nanoparticles from the vaginal lumen to draining lymph nodes to prevent the transmission of HIV in women. Other known examples include mucosal delivery of vaccines to induce immunity. In all cases, molecular and particle transport by means of diffusion and convective diffusion play a major role. The corresponding transport processes have common inherent regularities and are addressed in this review. Here we use nanoparticle delivery from the vaginal lumen to the lymph nodes as an example to address the many aspects of associated transport processes. In this case, nanoparticles penetrate the epithelial barrier and move through the interstitium (tissue) to the initial lymphatics until they finally reach the lymph nodes. Since the movement of interstitial liquid near the epithelial barrier is retarded, nanoparticle transport was found to take place through special foci present in the epithelium. Immediately after nanoparticles emerge from the foci, they move through the interstitium due to diffusion affected by convection (convective diffusion). Specifically, the convective transport of nanoparticles occurs due to their convection together with interstitial fluid through the interstitium toward the initial lymph capillaries. Afterwards, nanoparticles move together with the lymph flow along the initial lymph capillaries and then enter the afferent lymphatics and ultimately reach the lymph node. As the liquid moves through the interstitium toward the initial lymph capillaries due to the axial movement of lymph along the lymphatics, the theory for coupling between lymph flow and concomitant flow through the interstitium is developed to describe this general case. The developed theory is applied to interpret the large uptake of Qdots by lymph nodes during inflammation, which is induced by pre-treating mouse vagina with the surfactant Nonoxynol-9 prior to instilling the Qdots. Inflammation is viewed here to cause broadening of the pores within the interstitium with the concomitant formation of transport channels which function as conduits to transport the nanoparticles to the initial lymph capillaries. We introduced the term "effective channels" to denote those channels which interconnect with foci present in the epithelial barrier and which function to transport nanoparticles to initial lymph capillaries. The time of transport toward the lymph node, predicated by the theory, increases rapidly with increasing the distance y0 between the epithelial barrier and the initial lymph capillaries. Transport time is only a few hours, when y 0 is small, about some R (where R is the initial lymph capillary radius), due to the predomination of a rather rapid convection in this case. This transport time to the lymph nodes may be tens of hours (or longer) when y0 is essentially larger and the slow diffusion controls the transport rate in a zone not far from the epithelial barrier, where convection is weak at large y0. Accounting for transport by diffusion only, which is mainly considered in many relevant publications, is not sufficient to explain our nanoparticle uptake kinetics because the possibility of fast transport due to convection is overlooked. Our systematic investigations have revealed that the information about the main transport conditions, namely, y0 and the pore broadening up to the dimension of the interstitial transport channels, is necessary to create the quantitative model of enhanced transport during inflammation with the use of the proposed model as a prerequisite. The modeling for convective diffusion of nanoparticles from the epithelial barrier to the lymph node has been mainly accomplished here, while the diffusion only scenario is accounted for in other studies. This first modeling is a semi-quantitative one. A more rigorous mathematical approach is almost impossible at this stage because the transport properties of the model are introduced here for the first time. These properties include: discovery of foci in the epithelium, formation of transport channels, definition of channels interconnecting with foci (effective foci and channels), generation of flow in the interstitium toward the initial lymph capillaries due to axial flow within afferent lymphatics, deformation of this flow due to hydrodynamic impermeability of the squamous layer with the formation of the hydrodynamic stagnation zone near the epithelial barrier, predomination of slow diffusion transport within the above zone, and predomination of fast convection of nanoparticles near the initial lymph capillaries. © 2013 Elsevier B.V. All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 2.30M | Year: 2011

DESCRIPTION (provided by applicant): The clinical significance of chronic pro-inflammatory reactions in dialysis patients due to exposure to endotoxin has become a central issue in nephrology. The European Renal Association urges the routine use of ultrapure dialysate with bacteria and endotoxin levels of lt 0.1 CFU/ml and lt 0.03 EU/ml, respectively. In the US, the maximum allowable limit of bacteria in water is 200 cfu/ml and the maximum allowable limit for endotoxin is 2 EU/ml. Considering the clinicalimplications and risks of exposing dialysis patients to a high level of cytokine- inducing molecules on a continuous basis, the US needs to quickly move to adopt the ultrapure dialysate (UPD) ISO 1163:2009 Standard. However, considering the state of US dialysis water systems, meeting such standard will be impossible to achieve without adopting new technologies that can eradicate biofilm from the dialysis water systems and correcting some inherent deficiencies in current maintenance protocols. In this FastTrack application, we propose to develop an integrated strategy to produce UPD based on using our CleanFlow device which delivers the highly effective two-phase flow (TPF) process. This strategy must consider treating all the surfaces of the water systemto the point where the dialysate enters the dialyzer. In this project we will develop methods and protocols to test the integrated strategy in dialysis clinics. We will verify that we can reduce inflammation markers (IL-6 and CRP) in patients treated withdialysate made according to this new strategy. The integrated strategy will include: 1) cleaning the distribution loops with the TPF process, 2) replacing the connection tubing to dialysis machines with a cleaned and disinfected set each time, and 3) ensuring that dialysis machines are equipped with a retentive ultrafilter before the dialyzer. We will compare the results of our integrated strategy with conventional methods, and will assess the impact of using or not using the ultrafilter on the results. Weplan to also include testing for bacterial DNA fragments in the dialysate before and after the ultrafilter. Development of this integrated strategy to produce UPD in US dialysis clinics is expected to decrease the chronic inflammation state in dialysis patients and increase responsiveness to erythropoietin. PUBLIC HEALTH RELEVANCE: In this Fast Track application, we propose to develop an integrated strategy to produce ultrapure dialysate (UPD) based on our proven capability of effectively removing biofilm from dialysis water systems using the CleanFlow device which delivers the novel two-phase flow (TPF) process. The strategy and approach detailed in this application address the logistical issues that clinics must adhere to in order to be able to make UPD, including: 1) the use of a retentive ultrafilter before the dialyzer, and 2) changing the connection tubing to dialysis machines during each cleaning. The project is directed to developing the technology and protocols that will enable US clinics tomeet the ISO 1163:2009 standard for UPD. Success of this development will make it possible for clinics with PVC piping construction to meet the above ISO standard at a reasonable cost, and will translate into decreasing the level of inflammatory biomarkers in dialysis patients and into increasing responsiveness to erythropoietin.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.00M | Year: 2012

DESCRIPTION (provided by applicant): The clinical significance of chronic pro-inflammatory reactions in dialysis patients due to exposure to endotoxin has become a central issue in nephrology. The European Renal Association urges the routine use of ultrapure dialysate with bacteria and endotoxin levels of lt 0.1 CFU/ml and lt 0.03 EU/ml, respectively. In the US, the maximum allowable limit of bacteria in water is 200 cfu/ml and the maximum allowable limit for endotoxin is 2 EU/ml. Considering the clinicalimplications and risks of exposing dialysis patients to a high level of cytokine- inducing molecules on a continuous basis, the US needs to quickly move to adopt the ultrapure dialysate (UPD) ISO 1163:2009 Standard. However, considering the state of US dialysis water systems, meeting such standard will be impossible to achieve without adopting new technologies that can eradicate biofilm from the dialysis water systems and correcting some inherent deficiencies in current maintenance protocols. In this FastTrack application, we propose to develop an integrated strategy to produce UPD based on using our CleanFlow device which delivers the highly effective two-phase flow (TPF) process. This strategy must consider treating all the surfaces of the water systemto the point where the dialysate enters the dialyzer. In this project we will develop methods and protocols to test the integrated strategy in dialysis clinics. We will verify that we can reduce inflammation markers (IL-6 and CRP) in patients treated withdialysate made according to this new strategy. The integrated strategy will include: 1) cleaning the distribution loops with the TPF process, 2) replacing the connection tubing to dialysis machines with a cleaned and disinfected set each time, and 3) ensuring that dialysis machines are equipped with a retentive ultrafilter before the dialyzer. We will compare the results of our integrated strategy with conventional methods, and will assess the impact of using or not using the ultrafilter on the results. Weplan to also include testing for bacterial DNA fragments in the dialysate before and after the ultrafilter. Development of this integrated strategy to produce UPD in US dialysis clinics is expected to decrease the chronic inflammation state in dialysis patients and increase responsiveness to erythropoietin.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.98K | Year: 2010

DESCRIPTION (provided by applicant): We discovered a new modality that will allow us to effectively remove excess fluid from patients and manage hypervolemia. Accordingly, we propose the development of a simple, safe miniature portable device that can slowly remove sufficient excess fluid, on a continuous basis, from patients with congestive heart failure (CHF). During this two-year Phase I study, we will design and develop this new fluid removal process, and define the design requirements for the miniaturized device, which will include a replaceable component. This replaceable component will be designed and evaluated in an in vitro testing circuit. Measurement of inflammatory mediators and clotting factors will be made, along with the continuous monitoring of blood flow rate, and associated pressures at several points in the circuit will be made. Given that there are no such portable devices available for clinical use, this device will have strong potential for improving survival and for decreasing costs for patients with recalcitrant congestive heart failure. Aside from the implied benefit of controlling congestive heart failure and potentially reducing left ventricular hypertrophy (LVH), a major cause of morbidity and mortality in dialysis patients, this device would be expected to dramatically reduce the excess, repetitive hospitalizations commonly incurred by dialysis patients who suffer from fluid overload and pulmonary edema. Reducing the number of these emergency hospitalizations would undoubtedly be a major cost savings for the Medicare-funded End Stage Renal Disease (ESRD) and CHF treatments. PUBLIC HEALTH RELEVANCE: This proposal addresses the development of a portable hemofiltration device which can be attached to a central venous catheter for the purpose of providing slow, continuous fluid removal for the maintenance of fluid balance in patients on chronic dialysis. This device would have the most value for those dialysis patients who are having difficulty in controlling blood pressure, fluid retention and pulmonary edema. The proposed design is appealing, with the utilization of a replaceable filtration unit which can be easily attached to a propulsion unit with miniature pumps for propelling blood through a hemofilter. This design could easily allow for slow, continuous fluid removal (1-3 ml/min) throughout the interdialytic period, allowing dialysis patients to avoid fluid overload. Aside from the implied benefit of controlling congestive heart failure and potentially reducing left ventricular hypertrophy (LVH), a major cause of morbidity and mortality in dialysis patients, this device would be expected to dramatically reduce the excess, repetitive hospitalizations commonly incurred by dialysis patients who suffer from fluid overload and pulmonary edema. Reducing the number of these emergency hospitalizations would undoubtedly be a major cost savings for the Medicare-funded End Stage Renal Disease (ESRD) program. This device could also be used for the management of congestive heart failure (CHF) in patients who are not on dialysis but in whom emergency admissions for pulmonary edema are a common occurrence.


Trademark
Novaflux Technologies, Inc. | Date: 2013-01-08

Medical devices for dialyzer reprocessing, namely, sterilization units for medical purposes.


Trademark
Novaflux Technologies, Inc. | Date: 2013-01-08

cleaning solution for dialyzers.


Trademark
Novaflux Technologies, Inc. | Date: 2013-01-15

Sterilization units for medical purposes.


Trademark
Novaflux Technologies, Inc. | Date: 2013-01-15

Sterilization units for medical purposes.

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