Raymond Samuel - Academia.edu (original) (raw)

Papers by Raymond Samuel

Journal of Racial and Ethnic Health Disparities

The COVID-19 pandemic and its associated mitigation strategies have significant psychosocial, beh... more The COVID-19 pandemic and its associated mitigation strategies have significant psychosocial, behavioral, socioeconomic, and health impacts, particularly in vulnerable US populations. Different factors have been identified as influencers of the transmission rate; however, the effects of area deprivation index (as a measure of social determinants of health, SDoH) as a factor on COVID-19 disease early dynamics have not been established. We determined the effects of area deprivation index (ADI) and demographic factors on COVID-19 outcomes in Washington, D.C. This retrospective study used publicly available data on COVID-19 cases and mortality of Washington, D.C., during March 31st-July 4th, 2020. The main predictors included area deprivation index (ADI), age, and race/ethnicity. The ADI of each census block groups in D.C. (n=433) were obtained from Neighborhood Atlas map. Using a machine learning-based algorithm, the outcome variables were partitioned into time intervals: time duration (P i , days), rate of change coefficient (E i), and time segment load (P i ×E i) for transmission rate and mortality. Correlation analysis and multiple linear regression models were used to determine associations between predictors and outcome variables. COVID-19 early transmission rate (E 1) was highly correlated with ADI (SDoH; r= 0.88, p=0.0044) of the Washington, D.C. community. We also found positive association between ADI, age (0-17 years, r=0.91, p=0.0019), and race (African American/Black, r=0.86; p=0.0068) and COVID-19 outcomes. There was high variability in early transmission across the geographic regions (i.e., wards) of Washington, D.C., and this variability was driven by race/ ethnic composition and ADI. Understanding the association of COVID-19 disease early transmission and mortality dynamics and key socio-demographic risk factors such as age, race, and ADI, as a measure of social determinants, will contribute to health equity/equality and distribution of economic resources/assistance and is essential for future predictive modeling of the COVID-19 pandemic to limit morbidity and mortality.

Multi-layered composite films fabricated of plasmid DNA and hydrolytically degradable polycation ... more Multi-layered composite films fabricated of plasmid DNA and hydrolytically degradable polycation have considerable potential as a synthetic gene delivery system for localized non-viral transfection. Applications include various biomedical applications such as implant functionalization, specifically, as gene therapy in orthopedic implant-host bone integration. New bone formation can be promoted on the implant-bone interface if presented with appropriate growth factors. Bone formation and healing occurs through an extensive process of inflammation, reparation, formation, and remodeling. Development is controlled by various growth factors and can be promoted by transfection of wound sites with factors such as osteogenic BMPs. Since these factors play a role throughout the healing process, long-term gene delivery has great potential for promoting bone growth along different stages of reparation. We have developed polyelectrolyte multilayer (PEM) thin films whose initial and long-term re...

The avian egg shell membrane (ESM) is an abundant and environmentally friendly complex of two sem... more The avian egg shell membrane (ESM) is an abundant and environmentally friendly complex of two semi-permeable membranes, which are composed of highly cross-linked extra-cellular proteins. The ESM has been shown to be biocompatible and a potential biomaterial in tissue engineering applications. We have utilized ESM as scaffold for the delivery of non-viral vectors deposited within polyelectrolyte multilayer (PEM) thin films constructed by the alternating deposition of hydrolytically degradable polycations (poly -amino ester) and polyanions (plasmid DNA vectors). These ESM-PEM gene delivery devices progressively released the plasmid DNA sequentially deposited on the 3-D fibrous scaffold. The PEM-modified surfaces of the ESM were able to support the adhesion, proliferation and differentiation of MC3T3-E1 pre-osteoblast cells. The engrafted MC3T3-E1 cells were distributed throughout the full-thickness of the ESM and expressed the genes encoded in the plasmid DNA vectors. The increased su...

Human Gene Therapy, 2002

Our primary objective was to fabricate a porous gene-supplemented collagen-glycosaminoglycan (GSC... more Our primary objective was to fabricate a porous gene-supplemented collagen-glycosaminoglycan (GSCG) matrix for sustained delivery (over a period of several weeks) of plasmid DNA to articular chondrocytes when implanted into cartilage lesions. The specific aims of this in vitro study were to determine the release kinetics profiles of plasmid DNA from the GSCG matrices, and to determine the ability of the released plasmid DNA to transfect adult canine articular chondrocytes. In particular, we evaluated the effects of two variables, cross-linking treatment and the pH at which the DNA was incorporated into the matrices, on the amount of the plasmid DNA that remained bound to the GSCG matrices after passive (nonenzymatic) leaching and on the expression of a reporter gene in articular chondrocytes grown in the GSCG matrices. Collagen-glycosaminoglycan matrices were synthesized without cross-linking, and by three cross-linking treatments: dehydrothermal (DHT) treatment, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) treatment, and exposure to ultraviolet (UV) radiation. The plasmid DNA was incorporated into the collagen-glycosaminoglycan matrices in solutions at pH 2.5 or 7.5. Transmission electron microscopy studies revealed plasmid DNA bound to the walls of the porous GSCG matrices. In general, the GSCG matrices fabricated at pH 2.5 retained a larger fraction of the initial DNA load after 28 days of incubation in Tris-EDTA buffer. The passive, solvent-mediated release of the plasmid DNA from the GSCG matrices showed a biphasic pattern consisting of a faster, early release rate over the initial 8 hr of leaching followed by a slower, late release rate that was relatively constant over the subsequent 28 days of leaching. Electrophoretic analyses revealed that the plasmid DNA released from the GSCG matrices fabricated at pH 2.5 had been linearized and/or degraded; whereas the plasmid DNA leached from the GSCG matrices prepared with a DNA solution at pH 7.5 was primarily supercoiled and linear. Plasmid DNA released from all GSCG matrix formulations was able to generate luciferase reporter gene expression in monolayer-cultured chondrocytes transfected with the aid of a commercial lipid reagent, and in chondrocytes cultured in the GSCG matrices without the aid of a supplemental transfection reagent. Luciferase expression in chondrocyte-seeded GSCG constructs was evident throughout the culture period (28 days), with the EDC and UV cross-linked matrices prepared at pH 7.5 providing the highest transgene expression levels. We conclude that released plasmid DNA continually transfected canine articular chondrocytes seeded into GSCG matrices in vitro for a 4-week period as evidenced by luciferase reporter gene expression. Thus, GSCG matrices can be fabricated to provide sustained release of plasmid DNA carrying a potential therapeutic gene.

Biomaterials, 2011

Drug eluting coatings that can direct the host tissue response to implanted medical devices have ... more Drug eluting coatings that can direct the host tissue response to implanted medical devices have the potential to ameliorate both the medical and financial burden of complications from implantation. However, because many drugs useful in this arena are biologic in nature, a paucity of delivery strategies for biologics, including growth factors, currently limits the control that can be exerted on the implantation environment. Layer-by-Layer (LbL) polyelectrolyte multilayer films are highly attractive as ultrathin biologic reservoirs, due to conformal coating of difficult geometries, aqueous processing likely to preserve fragile protein function, and tenability of incorporation and release profiles. Herein, we describe the first LbL films capable of microgramscale release of the biologic Bone Morphogenetic Protein 2 (BMP-2), which is capable of directing the host tissue response to create bone from native progenitor cells. Ten micrograms of BMP-2 are released over a period of two weeks in vitro; less than 1% is released in the first 3 hours (compared with commercial collagen matrices which can release up to 60% of BMP-2, too quickly to induce differentiation). BMP-2 released from LbL films retains its ability to induce bone differentiation in MC3T3 E1S4 preosteoblasts, as measured by induction of alkaline phosphatase and stains for calcium (via Alizarin Red) and calcium matrix (via Von Kossa). In vivo, BMP-2 film coated scaffolds were compared with film coated scaffolds lacking BMP-2. BMP-2 coatings implanted intramuscularly were able to initiate host progenitor cells to differentiate into bone, which matured and expanded from four to nine weeks as measured by MicroCT and histology. Such LbL films represent new steps towards controlling and tuning host response to implanted medical devices, which may ultimately increase the success of implanted devices, provide alternative new approaches toward bone wound healing, and lay the foundation for development of a multi-therapeutic release coating.

Biomaterials, 2010

While the infection rate of orthopedic implants is low, the required treatment, which can involve... more While the infection rate of orthopedic implants is low, the required treatment, which can involve six weeks of antibiotic therapy and two additional surgical operations, is life threatening and expensive, and thus motivates the development of a one-stage re-implantation procedure. Polyelectrolyte multilayers incorporating gentamicin were fabricated using the layer-by-layer deposition process for use as a device coating to deal with an existing bone infection in a direct implant exchange operation. The films eluted about 70% of their payload in vitro during the first three days and subsequently continued to release drug for more than four additional weeks, reaching a total average release of over 550 μg/cm 2. The coatings were demonstrated to be bactericidal against Staphylococcus aureus, and degradation products were generally nontoxic towards MC3T3-E1 murine preosteoblasts. Film-coated titanium implants were compared to uncoated implants in an in vivo S. aureus bone infection model. After a direct exchange procedure, the antimicrobial-coated devices yielded bone homogenates with a significantly lower degree of infection than uncoated devices at both day four (p < 0.004) and day seven (p < 0.03). This study has demonstrated that a self-assembled ultrathin film coating is capable of effectively treating an experimental bone infection in vivo and lays the foundation for development of a multi-therapeutic film for optimized, synergistic treatment of pain, infection, and osteomyelitis.

Advanced Materials, 2010

A new strategy to create biodegradable drug-loaded coatings on microneedle patches, using a proce... more A new strategy to create biodegradable drug-loaded coatings on microneedle patches, using a process known as layer-by-layer (LbL) self-assembly, is reported on p. 4851 by Paula Hammond and coworkers. Water-soluble polymers are adsorbed with oppositely-charged drugs or ...

Advanced Materials, 2010

Current vaccine and therapeutic delivery is largely needle-based, [ 1 ] but a number of inherent ... more Current vaccine and therapeutic delivery is largely needle-based, [ 1 ] but a number of inherent risks and disadvantages to needle-based delivery have been recognized, such as the need for cold storage of liquid formulations, [ 1, 2 ] the requirement of trained personnel for administration, and reduced safety due to needle re-use and needle-based injuries. [ 3 ] To address these limitations, vaccination and therapeutics administration through the skin represents a promising alternative strategy, [ 4-6 ] and technologies promoting efficient transcutaneous delivery of a variety of drugs and vaccines has become a significant focus of recent research (reviewed in [ 7 ]). Recent work in this area has demonstrated the utility of microneedle arrays for efficient and pain-free disruption of the stratum corneum (SC), promoting transcutaneous delivery of a variety of bio-active materials. [ 8, 9 ] Microneedle delivery is often achieved by coating dried water-soluble drug formulations directly on the surfaces of solid microneedles. Parallel studies in the area of polyelectrolyte multilayer (PEM) engineering have demonstrated the potential for simple and versatile materials encapsulation into conformal thin films, providing robust control over materials release, solid-state stabilization of environmentally-sensitive encapsulated materials, and nanometer

Biomaterials, 2011

A promising strategy to accelerate joint implant integration and reduce recovery time and failure... more A promising strategy to accelerate joint implant integration and reduce recovery time and failure rates is to deliver a combination of certain growth factors to the integration site. There is a need to control the quantity of growth factors delivered at different times during the healing process to maximize efficacy. Polyelectrolyte multilayer (PEM) films, built using the layer-by-layer (LbL) technique, are attractive for releasing controlled amounts of potent growth factors over a sustained period. Here, we present PEM films that sequester physiological amounts of osteogenic rhBMP-2 (recombinant human bone morphogenetic protein-2) and angiogenic rhVEGF 165 (recombinant human vascular endothelial growth factor) in different ratios in a degradable [poly(β-amino ester)/ polyanion/growth factor/ polyanion] LbL tetralayer repeat architecture where the biologic load scaled linearly with the number of tetralayers. No burst release of either growth factor was observed as the films degraded. The release of rhBMP-2 was sustained over a period of 2 weeks, while rhVEGF 165 eluted from the film over the first 8 days. Both growth factors retained their efficacy, as quantified with relevant in vitro assays. rhBMP-2 initiated a dose dependent differentiation cascade in MC3T3-E1S4 pre-osteoblasts while rhVEGF 165 upregulated HUVEC proliferation, and accelerated closure of a scratch in HUVEC cell cultures in a dose dependent manner. In vivo, the mineral density of ectopic bone formed de novo by rhBMP-2/rhVEGF 165 PEM films was approximately 33% higher than when only rhBMP-2 was introduced, with a higher trabecular thickness, which would indicate a decrease in the risk of osteoporotic fracture. Bone formed throughout the scaffold when both growth factors were released, which suggests more complete remodeling due to an increased local vascular network. This study demonstrates a promising approach to delivering precise doses of multiple growth factors for a variety of implant applications where control over spatial and temporal release profile of the biologic is desired.

Biomaterials, 2011

The integration of orthopedic implants with host bone presents a major challenge in joint arthrop... more The integration of orthopedic implants with host bone presents a major challenge in joint arthroplasty, spinal fusion and tumor reconstruction. The cellular microenvironment can be programmed via implant surface functionalization allowing direct modulation of osteoblast adhesion, proliferation, and differentiation at the implant-bone interface. The development of layer-by-layer assembled polyelectrolyte multilayer (PEM) architectures has greatly expanded our ability to fabricate intricate nanometer to micron scale thin film coatings that conform to complex implant geometries. The in vivo therapeutic efficacy of thin PEM implant coatings for numerous biomedical applications has previously been reported. We have fabricated protamine-based PEM thin films that support the long-term proliferation and differentiation of pre-osteoblast cells on non-cross-linked film coated surfaces. These hydrophilic PEM functionalized surfaces with nanometer-scale roughness facilitated increased deposition of calcified matrix by osteoblasts in vitro, and thus offer the potential to enhance implant integration with host bone. The coatings can make an immediate impact in the osteogenic culture of stem cells and assessment of the osteogenic potential of new therapeutic factors.

Critical Care Medicine, 2021

2020 IEEE 21st International Conference on Information Reuse and Integration for Data Science (IRI), 2020

Giving care to persons with dementia (PwD) has a significant strain on the quality of life for fa... more Giving care to persons with dementia (PwD) has a significant strain on the quality of life for familial caregivers. Due to the overdependent nature of PwD, caregivers are burdened with health issues, stress, depression, loneliness, and social isolation. As a result, there is a need for understanding the nature and severity of this burden. In this paper, we introduce a novel data-driven approach based on machine learning modeling to ascertain caregiver burden using multimodal data from multitudinal sources. In particular, we propose to leverage data from smart devices, wearables, and psychometric surveys, to assess caregiver burden employing both shallow and deep neural network architectures.

SN Computer Science, 2021

The World Health Organization estimates that approximately 10 million people are newly diagnosed ... more The World Health Organization estimates that approximately 10 million people are newly diagnosed with dementia each year and a global prevalence of nearly 50 million persons with dementia (PwD). The vast majority of PwD living at home receive the majority of their care from informal familial caregivers. The quality of life (QOL) of familial caregivers may be significantly impacted by their caregiving responsibilities and resultant caregiver burden. A major contributor to caregiver burden is the random occurrence of agitation in PwD and familial caregivers' lack of preparedness to manage these episodes. Caregiver burden may be reduced if it is possible to forecast impending agitation episodes. In this study, we leverage datadriven deep learning models to predict agitation episodes in PwD. We used Long Short-Term Memory (LSTM), a deep learning class of algorithms, to forecast agitations up to 30 min before actual agitation events. In particular, we managed the missing data by estimating the missing values and compensated for the class imbalance challenge by down-sampling the majority class. The simulations were based on real-world data from Alzheimer's disease (AD) caregivers and PwD dyads home environments, including ambient noise level, illumination, room temperature, atmospheric pressure (Pa), and relative humidity. Our results show the efficacy of data-driven deep learning models in predicting agitation episodes in communitydwelling AD dyads with accuracy of 98.6% and recall (sensitivity) of 84.8%.

Proteins: Structure, Function, and Genetics, 2000

CC individuals, homozygous for the expression of ␤ C-globin, and SC individuals expressing both ␤... more CC individuals, homozygous for the expression of ␤ C-globin, and SC individuals expressing both ␤ S and ␤ C-globins, are known to form intraerythrocytic oxy hemoglobin tetragonal crystals with pathophysiologies specific to the phenotype. To date, the question remains as to why HbC forms in vivo crystals in the oxy state and not in the deoxy state. Our first approach is to study HbC crystallization in vitro, under non-physiological conditions. We present here a comparison of deoxy and oxy HbC crystal formation induced under conditions of concentrated phosphate buffer (2g% Hb, 1.8M potassium phosphate buffer) and viewed by differential interference contrast microscopy. Oxy HbC formed isotropic amorphous aggregates with subsequent tetragonal crystal formation. Also observed, but less numerous, were twisted, macro-ribbons that appeared to evolve into crystals. Deoxy HbC also formed aggregates and twisted macro-ribbon forms similar to those seen in the oxy liganded state. However, in contrast to oxy HbC, deoxy HbC favored the formation of a greater morphologic variety of aggregates including polymeric unbranched fibers in radial arrays with dense centers, with infrequent crystal formation in close spatial relation to both the radial arrays and macroribbons. Unlike the oxy (R-state) tetragonal crystal, deoxy HbC formed flat, hexagonal crystals. These results suggest: (1) the Lys substitution at ␤6 evokes a crystallization process dependent upon ligand state conformation [i.e., the R (oxy) or T (deoxy) allosteric conformation]; and (2) the oxy ligand state is thermodynamically driven to a limited number of aggregation pathways with a high propensity to form the tetragonal crystal structure. This is in contrast to the deoxy form of HbC that energetically equally favors multiple pathways of aggregation, not all of which might culminate in crystal formation. Proteins 2001; 42:99-107.

Nature, 1990

Deoxygenated sickle haemoglobin polymerizes into long 210-A diameter fibres that distort and decr... more Deoxygenated sickle haemoglobin polymerizes into long 210-A diameter fibres that distort and decrease the deformability of red blood cells, and cause sickle cell disease. The fibres consist of seven intertwined double strands. They can form birefringent nematic liquid crystals (tactoids) and spherulites. Rheologically, the system behaves as a gel. The equilibria show a phase separation and a solubility. The reaction kinetics show a delay time, are then roughly exponential and are highly dependent on concentration and temperature, and accord with the double nucleation model. But these conclusions are derived from macroscopic data, without direct observation of individual fibres. We have now used non-invasive video-enhanced differential interference contrast (DIC) and dark-field microscopy to observe nucleation, growth and interaction of sickle deoxyhaemoglobin fibres in real time. The fibres originate both from centres that produce many radially distributed fibres and on the surface of pre-existing fibres, from which they then branch. The resulting network is cross-linked and dynamic in that it is flexible and continues to grow and cross-link. Our results support most aspects of the double nucleation model.

Biochemical and Biophysical Research Communications, 2005

We investigated the effects of short-(8-and 24-h) and long-term (3 weeks) exposure to systemic no... more We investigated the effects of short-(8-and 24-h) and long-term (3 weeks) exposure to systemic normobaric hypoxia (13%) on the gene expression level of structural proteins and growth factors in knee joint cartilage of rabbits. Collagen type Ia2, II, and Va1, TGF-b1, and b-FGF were upregulated after short-term hypoxia in both menisci, but not in articular cartilage. In contrast, longterm hypoxia downregulated gene expression level of collagens, aggrecan, and growth factors in articular cartilage and meniscal fibrocartilage. Interestingly, gene expression levels of non-collagenous proteins biglycan, decorin, and versican were not affected by short-term or by long-term hypoxia in knee joint cartilage. The present study suggests that changes in oxygen level differentially affect gene expression levels of growth factors, collagens, and non-collagenous proteins in normal knee joint cartilage in rabbits.

Journal of Racial and Ethnic Health Disparities

The COVID-19 pandemic and its associated mitigation strategies have significant psychosocial, beh... more The COVID-19 pandemic and its associated mitigation strategies have significant psychosocial, behavioral, socioeconomic, and health impacts, particularly in vulnerable US populations. Different factors have been identified as influencers of the transmission rate; however, the effects of area deprivation index (as a measure of social determinants of health, SDoH) as a factor on COVID-19 disease early dynamics have not been established. We determined the effects of area deprivation index (ADI) and demographic factors on COVID-19 outcomes in Washington, D.C. This retrospective study used publicly available data on COVID-19 cases and mortality of Washington, D.C., during March 31st-July 4th, 2020. The main predictors included area deprivation index (ADI), age, and race/ethnicity. The ADI of each census block groups in D.C. (n=433) were obtained from Neighborhood Atlas map. Using a machine learning-based algorithm, the outcome variables were partitioned into time intervals: time duration (P i , days), rate of change coefficient (E i), and time segment load (P i ×E i) for transmission rate and mortality. Correlation analysis and multiple linear regression models were used to determine associations between predictors and outcome variables. COVID-19 early transmission rate (E 1) was highly correlated with ADI (SDoH; r= 0.88, p=0.0044) of the Washington, D.C. community. We also found positive association between ADI, age (0-17 years, r=0.91, p=0.0019), and race (African American/Black, r=0.86; p=0.0068) and COVID-19 outcomes. There was high variability in early transmission across the geographic regions (i.e., wards) of Washington, D.C., and this variability was driven by race/ ethnic composition and ADI. Understanding the association of COVID-19 disease early transmission and mortality dynamics and key socio-demographic risk factors such as age, race, and ADI, as a measure of social determinants, will contribute to health equity/equality and distribution of economic resources/assistance and is essential for future predictive modeling of the COVID-19 pandemic to limit morbidity and mortality.

Multi-layered composite films fabricated of plasmid DNA and hydrolytically degradable polycation ... more Multi-layered composite films fabricated of plasmid DNA and hydrolytically degradable polycation have considerable potential as a synthetic gene delivery system for localized non-viral transfection. Applications include various biomedical applications such as implant functionalization, specifically, as gene therapy in orthopedic implant-host bone integration. New bone formation can be promoted on the implant-bone interface if presented with appropriate growth factors. Bone formation and healing occurs through an extensive process of inflammation, reparation, formation, and remodeling. Development is controlled by various growth factors and can be promoted by transfection of wound sites with factors such as osteogenic BMPs. Since these factors play a role throughout the healing process, long-term gene delivery has great potential for promoting bone growth along different stages of reparation. We have developed polyelectrolyte multilayer (PEM) thin films whose initial and long-term re...

The avian egg shell membrane (ESM) is an abundant and environmentally friendly complex of two sem... more The avian egg shell membrane (ESM) is an abundant and environmentally friendly complex of two semi-permeable membranes, which are composed of highly cross-linked extra-cellular proteins. The ESM has been shown to be biocompatible and a potential biomaterial in tissue engineering applications. We have utilized ESM as scaffold for the delivery of non-viral vectors deposited within polyelectrolyte multilayer (PEM) thin films constructed by the alternating deposition of hydrolytically degradable polycations (poly -amino ester) and polyanions (plasmid DNA vectors). These ESM-PEM gene delivery devices progressively released the plasmid DNA sequentially deposited on the 3-D fibrous scaffold. The PEM-modified surfaces of the ESM were able to support the adhesion, proliferation and differentiation of MC3T3-E1 pre-osteoblast cells. The engrafted MC3T3-E1 cells were distributed throughout the full-thickness of the ESM and expressed the genes encoded in the plasmid DNA vectors. The increased su...

Human Gene Therapy, 2002

Our primary objective was to fabricate a porous gene-supplemented collagen-glycosaminoglycan (GSC... more Our primary objective was to fabricate a porous gene-supplemented collagen-glycosaminoglycan (GSCG) matrix for sustained delivery (over a period of several weeks) of plasmid DNA to articular chondrocytes when implanted into cartilage lesions. The specific aims of this in vitro study were to determine the release kinetics profiles of plasmid DNA from the GSCG matrices, and to determine the ability of the released plasmid DNA to transfect adult canine articular chondrocytes. In particular, we evaluated the effects of two variables, cross-linking treatment and the pH at which the DNA was incorporated into the matrices, on the amount of the plasmid DNA that remained bound to the GSCG matrices after passive (nonenzymatic) leaching and on the expression of a reporter gene in articular chondrocytes grown in the GSCG matrices. Collagen-glycosaminoglycan matrices were synthesized without cross-linking, and by three cross-linking treatments: dehydrothermal (DHT) treatment, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) treatment, and exposure to ultraviolet (UV) radiation. The plasmid DNA was incorporated into the collagen-glycosaminoglycan matrices in solutions at pH 2.5 or 7.5. Transmission electron microscopy studies revealed plasmid DNA bound to the walls of the porous GSCG matrices. In general, the GSCG matrices fabricated at pH 2.5 retained a larger fraction of the initial DNA load after 28 days of incubation in Tris-EDTA buffer. The passive, solvent-mediated release of the plasmid DNA from the GSCG matrices showed a biphasic pattern consisting of a faster, early release rate over the initial 8 hr of leaching followed by a slower, late release rate that was relatively constant over the subsequent 28 days of leaching. Electrophoretic analyses revealed that the plasmid DNA released from the GSCG matrices fabricated at pH 2.5 had been linearized and/or degraded; whereas the plasmid DNA leached from the GSCG matrices prepared with a DNA solution at pH 7.5 was primarily supercoiled and linear. Plasmid DNA released from all GSCG matrix formulations was able to generate luciferase reporter gene expression in monolayer-cultured chondrocytes transfected with the aid of a commercial lipid reagent, and in chondrocytes cultured in the GSCG matrices without the aid of a supplemental transfection reagent. Luciferase expression in chondrocyte-seeded GSCG constructs was evident throughout the culture period (28 days), with the EDC and UV cross-linked matrices prepared at pH 7.5 providing the highest transgene expression levels. We conclude that released plasmid DNA continually transfected canine articular chondrocytes seeded into GSCG matrices in vitro for a 4-week period as evidenced by luciferase reporter gene expression. Thus, GSCG matrices can be fabricated to provide sustained release of plasmid DNA carrying a potential therapeutic gene.

Biomaterials, 2011

Drug eluting coatings that can direct the host tissue response to implanted medical devices have ... more Drug eluting coatings that can direct the host tissue response to implanted medical devices have the potential to ameliorate both the medical and financial burden of complications from implantation. However, because many drugs useful in this arena are biologic in nature, a paucity of delivery strategies for biologics, including growth factors, currently limits the control that can be exerted on the implantation environment. Layer-by-Layer (LbL) polyelectrolyte multilayer films are highly attractive as ultrathin biologic reservoirs, due to conformal coating of difficult geometries, aqueous processing likely to preserve fragile protein function, and tenability of incorporation and release profiles. Herein, we describe the first LbL films capable of microgramscale release of the biologic Bone Morphogenetic Protein 2 (BMP-2), which is capable of directing the host tissue response to create bone from native progenitor cells. Ten micrograms of BMP-2 are released over a period of two weeks in vitro; less than 1% is released in the first 3 hours (compared with commercial collagen matrices which can release up to 60% of BMP-2, too quickly to induce differentiation). BMP-2 released from LbL films retains its ability to induce bone differentiation in MC3T3 E1S4 preosteoblasts, as measured by induction of alkaline phosphatase and stains for calcium (via Alizarin Red) and calcium matrix (via Von Kossa). In vivo, BMP-2 film coated scaffolds were compared with film coated scaffolds lacking BMP-2. BMP-2 coatings implanted intramuscularly were able to initiate host progenitor cells to differentiate into bone, which matured and expanded from four to nine weeks as measured by MicroCT and histology. Such LbL films represent new steps towards controlling and tuning host response to implanted medical devices, which may ultimately increase the success of implanted devices, provide alternative new approaches toward bone wound healing, and lay the foundation for development of a multi-therapeutic release coating.

Biomaterials, 2010

While the infection rate of orthopedic implants is low, the required treatment, which can involve... more While the infection rate of orthopedic implants is low, the required treatment, which can involve six weeks of antibiotic therapy and two additional surgical operations, is life threatening and expensive, and thus motivates the development of a one-stage re-implantation procedure. Polyelectrolyte multilayers incorporating gentamicin were fabricated using the layer-by-layer deposition process for use as a device coating to deal with an existing bone infection in a direct implant exchange operation. The films eluted about 70% of their payload in vitro during the first three days and subsequently continued to release drug for more than four additional weeks, reaching a total average release of over 550 μg/cm 2. The coatings were demonstrated to be bactericidal against Staphylococcus aureus, and degradation products were generally nontoxic towards MC3T3-E1 murine preosteoblasts. Film-coated titanium implants were compared to uncoated implants in an in vivo S. aureus bone infection model. After a direct exchange procedure, the antimicrobial-coated devices yielded bone homogenates with a significantly lower degree of infection than uncoated devices at both day four (p < 0.004) and day seven (p < 0.03). This study has demonstrated that a self-assembled ultrathin film coating is capable of effectively treating an experimental bone infection in vivo and lays the foundation for development of a multi-therapeutic film for optimized, synergistic treatment of pain, infection, and osteomyelitis.

Advanced Materials, 2010

A new strategy to create biodegradable drug-loaded coatings on microneedle patches, using a proce... more A new strategy to create biodegradable drug-loaded coatings on microneedle patches, using a process known as layer-by-layer (LbL) self-assembly, is reported on p. 4851 by Paula Hammond and coworkers. Water-soluble polymers are adsorbed with oppositely-charged drugs or ...

Advanced Materials, 2010

Current vaccine and therapeutic delivery is largely needle-based, [ 1 ] but a number of inherent ... more Current vaccine and therapeutic delivery is largely needle-based, [ 1 ] but a number of inherent risks and disadvantages to needle-based delivery have been recognized, such as the need for cold storage of liquid formulations, [ 1, 2 ] the requirement of trained personnel for administration, and reduced safety due to needle re-use and needle-based injuries. [ 3 ] To address these limitations, vaccination and therapeutics administration through the skin represents a promising alternative strategy, [ 4-6 ] and technologies promoting efficient transcutaneous delivery of a variety of drugs and vaccines has become a significant focus of recent research (reviewed in [ 7 ]). Recent work in this area has demonstrated the utility of microneedle arrays for efficient and pain-free disruption of the stratum corneum (SC), promoting transcutaneous delivery of a variety of bio-active materials. [ 8, 9 ] Microneedle delivery is often achieved by coating dried water-soluble drug formulations directly on the surfaces of solid microneedles. Parallel studies in the area of polyelectrolyte multilayer (PEM) engineering have demonstrated the potential for simple and versatile materials encapsulation into conformal thin films, providing robust control over materials release, solid-state stabilization of environmentally-sensitive encapsulated materials, and nanometer

Biomaterials, 2011

A promising strategy to accelerate joint implant integration and reduce recovery time and failure... more A promising strategy to accelerate joint implant integration and reduce recovery time and failure rates is to deliver a combination of certain growth factors to the integration site. There is a need to control the quantity of growth factors delivered at different times during the healing process to maximize efficacy. Polyelectrolyte multilayer (PEM) films, built using the layer-by-layer (LbL) technique, are attractive for releasing controlled amounts of potent growth factors over a sustained period. Here, we present PEM films that sequester physiological amounts of osteogenic rhBMP-2 (recombinant human bone morphogenetic protein-2) and angiogenic rhVEGF 165 (recombinant human vascular endothelial growth factor) in different ratios in a degradable [poly(β-amino ester)/ polyanion/growth factor/ polyanion] LbL tetralayer repeat architecture where the biologic load scaled linearly with the number of tetralayers. No burst release of either growth factor was observed as the films degraded. The release of rhBMP-2 was sustained over a period of 2 weeks, while rhVEGF 165 eluted from the film over the first 8 days. Both growth factors retained their efficacy, as quantified with relevant in vitro assays. rhBMP-2 initiated a dose dependent differentiation cascade in MC3T3-E1S4 pre-osteoblasts while rhVEGF 165 upregulated HUVEC proliferation, and accelerated closure of a scratch in HUVEC cell cultures in a dose dependent manner. In vivo, the mineral density of ectopic bone formed de novo by rhBMP-2/rhVEGF 165 PEM films was approximately 33% higher than when only rhBMP-2 was introduced, with a higher trabecular thickness, which would indicate a decrease in the risk of osteoporotic fracture. Bone formed throughout the scaffold when both growth factors were released, which suggests more complete remodeling due to an increased local vascular network. This study demonstrates a promising approach to delivering precise doses of multiple growth factors for a variety of implant applications where control over spatial and temporal release profile of the biologic is desired.

Biomaterials, 2011

The integration of orthopedic implants with host bone presents a major challenge in joint arthrop... more The integration of orthopedic implants with host bone presents a major challenge in joint arthroplasty, spinal fusion and tumor reconstruction. The cellular microenvironment can be programmed via implant surface functionalization allowing direct modulation of osteoblast adhesion, proliferation, and differentiation at the implant-bone interface. The development of layer-by-layer assembled polyelectrolyte multilayer (PEM) architectures has greatly expanded our ability to fabricate intricate nanometer to micron scale thin film coatings that conform to complex implant geometries. The in vivo therapeutic efficacy of thin PEM implant coatings for numerous biomedical applications has previously been reported. We have fabricated protamine-based PEM thin films that support the long-term proliferation and differentiation of pre-osteoblast cells on non-cross-linked film coated surfaces. These hydrophilic PEM functionalized surfaces with nanometer-scale roughness facilitated increased deposition of calcified matrix by osteoblasts in vitro, and thus offer the potential to enhance implant integration with host bone. The coatings can make an immediate impact in the osteogenic culture of stem cells and assessment of the osteogenic potential of new therapeutic factors.

Critical Care Medicine, 2021

2020 IEEE 21st International Conference on Information Reuse and Integration for Data Science (IRI), 2020

Giving care to persons with dementia (PwD) has a significant strain on the quality of life for fa... more Giving care to persons with dementia (PwD) has a significant strain on the quality of life for familial caregivers. Due to the overdependent nature of PwD, caregivers are burdened with health issues, stress, depression, loneliness, and social isolation. As a result, there is a need for understanding the nature and severity of this burden. In this paper, we introduce a novel data-driven approach based on machine learning modeling to ascertain caregiver burden using multimodal data from multitudinal sources. In particular, we propose to leverage data from smart devices, wearables, and psychometric surveys, to assess caregiver burden employing both shallow and deep neural network architectures.

SN Computer Science, 2021

The World Health Organization estimates that approximately 10 million people are newly diagnosed ... more The World Health Organization estimates that approximately 10 million people are newly diagnosed with dementia each year and a global prevalence of nearly 50 million persons with dementia (PwD). The vast majority of PwD living at home receive the majority of their care from informal familial caregivers. The quality of life (QOL) of familial caregivers may be significantly impacted by their caregiving responsibilities and resultant caregiver burden. A major contributor to caregiver burden is the random occurrence of agitation in PwD and familial caregivers' lack of preparedness to manage these episodes. Caregiver burden may be reduced if it is possible to forecast impending agitation episodes. In this study, we leverage datadriven deep learning models to predict agitation episodes in PwD. We used Long Short-Term Memory (LSTM), a deep learning class of algorithms, to forecast agitations up to 30 min before actual agitation events. In particular, we managed the missing data by estimating the missing values and compensated for the class imbalance challenge by down-sampling the majority class. The simulations were based on real-world data from Alzheimer's disease (AD) caregivers and PwD dyads home environments, including ambient noise level, illumination, room temperature, atmospheric pressure (Pa), and relative humidity. Our results show the efficacy of data-driven deep learning models in predicting agitation episodes in communitydwelling AD dyads with accuracy of 98.6% and recall (sensitivity) of 84.8%.

Proteins: Structure, Function, and Genetics, 2000

CC individuals, homozygous for the expression of ␤ C-globin, and SC individuals expressing both ␤... more CC individuals, homozygous for the expression of ␤ C-globin, and SC individuals expressing both ␤ S and ␤ C-globins, are known to form intraerythrocytic oxy hemoglobin tetragonal crystals with pathophysiologies specific to the phenotype. To date, the question remains as to why HbC forms in vivo crystals in the oxy state and not in the deoxy state. Our first approach is to study HbC crystallization in vitro, under non-physiological conditions. We present here a comparison of deoxy and oxy HbC crystal formation induced under conditions of concentrated phosphate buffer (2g% Hb, 1.8M potassium phosphate buffer) and viewed by differential interference contrast microscopy. Oxy HbC formed isotropic amorphous aggregates with subsequent tetragonal crystal formation. Also observed, but less numerous, were twisted, macro-ribbons that appeared to evolve into crystals. Deoxy HbC also formed aggregates and twisted macro-ribbon forms similar to those seen in the oxy liganded state. However, in contrast to oxy HbC, deoxy HbC favored the formation of a greater morphologic variety of aggregates including polymeric unbranched fibers in radial arrays with dense centers, with infrequent crystal formation in close spatial relation to both the radial arrays and macroribbons. Unlike the oxy (R-state) tetragonal crystal, deoxy HbC formed flat, hexagonal crystals. These results suggest: (1) the Lys substitution at ␤6 evokes a crystallization process dependent upon ligand state conformation [i.e., the R (oxy) or T (deoxy) allosteric conformation]; and (2) the oxy ligand state is thermodynamically driven to a limited number of aggregation pathways with a high propensity to form the tetragonal crystal structure. This is in contrast to the deoxy form of HbC that energetically equally favors multiple pathways of aggregation, not all of which might culminate in crystal formation. Proteins 2001; 42:99-107.

Nature, 1990

Deoxygenated sickle haemoglobin polymerizes into long 210-A diameter fibres that distort and decr... more Deoxygenated sickle haemoglobin polymerizes into long 210-A diameter fibres that distort and decrease the deformability of red blood cells, and cause sickle cell disease. The fibres consist of seven intertwined double strands. They can form birefringent nematic liquid crystals (tactoids) and spherulites. Rheologically, the system behaves as a gel. The equilibria show a phase separation and a solubility. The reaction kinetics show a delay time, are then roughly exponential and are highly dependent on concentration and temperature, and accord with the double nucleation model. But these conclusions are derived from macroscopic data, without direct observation of individual fibres. We have now used non-invasive video-enhanced differential interference contrast (DIC) and dark-field microscopy to observe nucleation, growth and interaction of sickle deoxyhaemoglobin fibres in real time. The fibres originate both from centres that produce many radially distributed fibres and on the surface of pre-existing fibres, from which they then branch. The resulting network is cross-linked and dynamic in that it is flexible and continues to grow and cross-link. Our results support most aspects of the double nucleation model.

Biochemical and Biophysical Research Communications, 2005

We investigated the effects of short-(8-and 24-h) and long-term (3 weeks) exposure to systemic no... more We investigated the effects of short-(8-and 24-h) and long-term (3 weeks) exposure to systemic normobaric hypoxia (13%) on the gene expression level of structural proteins and growth factors in knee joint cartilage of rabbits. Collagen type Ia2, II, and Va1, TGF-b1, and b-FGF were upregulated after short-term hypoxia in both menisci, but not in articular cartilage. In contrast, longterm hypoxia downregulated gene expression level of collagens, aggrecan, and growth factors in articular cartilage and meniscal fibrocartilage. Interestingly, gene expression levels of non-collagenous proteins biglycan, decorin, and versican were not affected by short-term or by long-term hypoxia in knee joint cartilage. The present study suggests that changes in oxygen level differentially affect gene expression levels of growth factors, collagens, and non-collagenous proteins in normal knee joint cartilage in rabbits.