In JoVE (1)

Other Publications (105)

Articles by Subbu S. Venkatraman in JoVE

Other articles by Subbu S. Venkatraman on PubMed

In Vitro Study of Release Mechanisms of Paclitaxel and Rapamycin from Drug-incorporated Biodegradable Stent Matrices

Journal of Controlled Release : Official Journal of the Controlled Release Society. Jul, 2004  |  Pubmed ID: 15245890

We have studied the in vitro release kinetics of two important antirestenosis drugs from biodegradable stent matrices. A helical stent incorporating drugs was exposed to buffer, and both degradation-controlled and diffusion-controlled drug releases were observed. New methods for in vitro drug release for both paclitaxel and rapamycin have been developed. The release profile shows a slow diffusion-controlled phase, followed by a more rapid degradation-controlled region. In the early part of the drug release, no burst effect is observed for either drug. This might be significant for paclitaxel administration, where cardiotoxicity has been sometimes of concern. By suitable polymer/drug formulations, it is possible to develop controlled release stent matrices that can exhibit a variety of release profiles. These release profiles may have relevance to antirestenotic effects and to local or systemic toxic effects.

Controlled Release from Bioerodible Polymers: Effect of Drug Type and Polymer Composition

Journal of Controlled Release : Official Journal of the Controlled Release Society. Feb, 2005  |  Pubmed ID: 15653155

The effect of the chemical nature of the drug on matrix degradation and drug release behavior of degradable polymers was studied, using lidocaine as a model drug in base and salt forms. We show in this study that the drug in the base form has a substantial effect on the release characteristics, through an accelerating effect on matrix degradation. Study of drug release from PdlLGA shows that lidocaine salt follows a three-phase release pattern, in contrast to the biphasic release of the lidobase. However, PlLA shows a different drug release pattern, with only a single diffusion phase exhibited for both lidobase and lidosalt. We also demonstrate that the crystallinity of matrix plays an important role on drug release profiles: a crystalline matrix (PlLA IV=2.04) releases the drug at a much slower rate compared to its amorphous counterpart of similar molecular weight (PdlLA IV=2.4). The details of the study of different factors influencing the drug release may have important implications for the control of delivery of potent drugs in various therapeutic windows.

Micelle-like Nanoparticles of PLA-PEG-PLA Triblock Copolymer As Chemotherapeutic Carrier

International Journal of Pharmaceutics. Jul, 2005  |  Pubmed ID: 15946811

Triblock copolymer PLA-PEG-PLA were synthesized using ring opening polymerization with different LA/EG ratio. Micellar aggregates were prepared from these block copolymers and characterized. The degradation characteristics of selected copolymers were assessed in both micellar and film forms. Surface segregation of PEG was also quantified as a function of copolymer composition. Anti-cancer drugs 5-FU and paclitaxel were loaded into the micellar nanospheres with good efficiency. The drug release profile showed good control over the release of paclitaxel from these polymers.

Micelle-like Nanoparticles of Star-branched PEO-PLA Copolymers As Chemotherapeutic Carrier

Journal of Controlled Release : Official Journal of the Controlled Release Society. Dec, 2005  |  Pubmed ID: 16289421

Four-armed (star-branched) block copolymers of l-PLA and PEO were synthesized using ring opening polymerization with different LA/EO ratio. Micellar aggregates were prepared from these block copolymers and characterized. Some surface segregation of PEG was found : the extent depends on the state of the material (whether it is in film or particle form), as well as on molecular geometry. The degradation behavior of star-shaped copolymer was studied over a three week period and compared to its linear counterpart. Anti-cancer drugs 5-FU and paclitaxel were loaded into the micellar nanoparticles. The drug release profile showed that the release of paclitaxel from these polymers could be controlled over 2 weeks. The kinetics of drug release for star-branched, tri- and di-block copolymers were compared. The micelles from star-shaped branch showed more complete release of drug than the diblock copolymers; also, the lower hydrodynamic radius of star-shaped polymers may result in better clearance of the carrier polymer from the body.

Biodegradable Stents with Elastic Memory

Biomaterials. Mar, 2006  |  Pubmed ID: 16181673

This work reports, for the first time, the development of a fully biodegradable polymeric stent that can self-expand at body temperatures (approximately 37 degrees C), using the concept of elastic memory. This self-expansion is necessary in fully polymeric stents, to overcome the problem of elastic recoil following balloon expansion in a body vessel. Bi-layered biodegradable stent prototypes were produced from poly-L-lactic acid (PLLA) and poly glycolic acid (PLGA) polymers. Elastic memory was imparted to the stents by temperature conditioning. The thickness and composition of each layer in the stents are critical parameters that affect the rate of self-expansion at 37 degrees C, as well as the collapse strengths of the stents. The rate of self-expansion of the stents, as measured at 37 degrees C, exhibits a maximum with layer thickness. The Tg of the outer layer is another significant parameter that affects the overall rate of expansion.

Collapse Pressures of Bilayered Biodegradable Stents

Journal of Biomedical Materials Research. Part B, Applied Biomaterials. Oct, 2006  |  Pubmed ID: 16544311

Biodegradable helicoidal stent prototypes made up of layers of poly-L-lactic acid (PLLA) and poly(L-lactic-co-glycolic acid) (PLGA) polymers were fabricated by temperature conditioning the stents at different stages of fabrication. The process incorporated elastic memory, or self-expandability in the stent, which is desirable to minimize stent recoil. The collapse pressures of such stents were studied, with and without in vitro degradation. The effects of thickness and the composition of each layer on the collapse pressure were modeled using the simple series model. Results of the in vitro studies for over 3 months showed that collapse pressure of the stents depended mainly on the degradation and other side-effects brought about by the degradation of different polymer compositions. Generally, the trend is dominated by the thicker of the two layers that were used to form the stents.

Effect of Radio-opaque Filler on Biodegradable Stent Properties

Journal of Biomedical Materials Research. Part A. Oct, 2006  |  Pubmed ID: 16758453

The effect of the addition of a radio-opaque filler, barium sulfate (BaSO(4)), on the mechanical properties of a biodegradable amorphous polymer film (poly-lactic-co-glycolic acid, PLGA) was studied, as a function of degradation. With up to about 18% loading (v/v), the modulus of the filled polymer increases; beyond this concentration, agglomerates are formed. The filled systems are also radio-opaque, over a thickness range of 0.07-0.19 mm in stent form (helicoidal). These stents were then immersed in phosphate buffer pH 7.4 at 37(o)C for 2 weeks. The radial strength of stent was measured by using a compression test. It was found that filler-loaded stent (FS) increased in radial strength by about 4 times (14.95 +/- 1.20 N/mm) compared to the unfilled stent (UFS). However, both samples lost radial strength as the polymer degraded in buffer, but FS retained 60% (9.05 +/- 0.07 N/mm) of its strength after 2 weeks whereas only 36% (1.39 +/- 1.04 N/mm) was retained for UFS. Moreover, UFS lost its helical shape after 3 weeks. The findings have implications for optimization of degradable stent formulations.

Controlled Release of Sirolimus from a Multilayered PLGA Stent Matrix

Biomaterials. Nov, 2006  |  Pubmed ID: 16879865

The release of sirolimus from a bi-layer biodegradable polymeric film is reported in this study. Approved drug-eluting metal stents use a thin polymer coating to control drug release, but the degree of control is limited. In a fully polymeric stent, the use of multilayers allows a range of release kinetics. A bi-layer system, with PLLA as the supporting layer and PLGA as the drug-eluting layer, was used in this study to simulate release of sirolimus from a stent. The results show that the release of sirolimus is diffusion and degradation-controlled, and that the amount of sirolimus loading does not affect its release kinetics. The release of sirolimus is, however, accelerated by the addition of a plasticizer, such as PEG, as water uptake is increased. An increased water uptake increases polymer degradation, and changes the dominant mode of release to degradation-control. The release of sirolimus can, on the other hand, be retarded by using a coating of a biodegradable polyester with a lauryl ester end group. Therefore, multilayered systems offer many options for controlling sirolimus release over months.

Sustained Release of Hydrophobic and Hydrophilic Drugs from a Floating Dosage Form

International Journal of Pharmaceutics. May, 2007  |  Pubmed ID: 17194555

Floating dosage forms enable the sustained delivery of drugs in the gastro-intestinal tract. In this study, a type of multi-unit floating gel bead was synthesized with calcium alginate, sunflower oil, and a drug of interest through an emulsification/gelation process. The alginate beads with oil addition were able to continuously float over the medium for 24h under constant agitation while the non-oily beads could not. Three kinds of drugs with different hydrophilicities, ibuprofen, niacinamide and metoclopramide HCl, were tested in the study. The hydrophobic drug ibuprofen was released in a sustained manner for 24h, due to the oil partitioning. With suitable modification, the beads were able to also release the hydrophilic drugs, niacinamide and metoclopramide HCl, for a similar duration. Therefore a floating dosage form that is able to sustain release both hydrophobic and hydrophilic drugs within its extended gastric retention time has been developed.

A Novel Approach for the Control of Drug Release Rate Through Hydrogel Membrane: I. Effect of Drug Immobilization on Drug Release Rate by Copolymerization Method

European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V. Mar, 2008  |  Pubmed ID: 17826045

Precise control of drug release rate in hydrogel drug delivery systems to better mimic physiological condition is a challenging research topic in development of Advanced Drug Delivery Systems. One of the major issues with bioresponsive drug delivery systems is the excessive 'leakage' of drug while the system is in the 'off' state, which leads to shortening of the device life-time and potential overdose problem for the patient. In the present study, a new approach, based on partition effects, termed drug immobilization via copolymerization, is proposed to control the drug release rate of membrane-based drug delivery systems. In this method, a certain level of drug is pre-immobilized in the membrane through copolymerization. The immobilized drug contributes to the overall chemical potential of drug molecules in the membrane but their mobility is restricted, hence will not be released. At equilibrium, the amount of drug from donor that dissolved in the membrane is reduced due to contribution of immobilized drug, resulting in an effective reduction in partition coefficient and hence the release rate. The testing of the method by bovine serum albumin (BSA) as a model drug confirmed the controllability of the method: almost 35% reduction of the drug leakage in the 'off-state' was observed when 20mg BSA was immobilized in the pH-sensitive hydrogel membrane. The mathematical model of the drug partition in the membrane was modified to describe the new partition phenomenon (mobile drug and immobilized drug in the membrane) in this study.

Paclitaxel Release from Single and Double-layered Poly(DL-lactide-co-glycolide)/poly(L-lactide) Film for Biodegradable Coronary Stent Application

Journal of Biomedical Materials Research. Part A. Oct, 2008  |  Pubmed ID: 18080309

Our laboratory has been developing a completely biodegradable coronary stent which is made of bilayers of biodegradable polyesters. This article presents the preliminary work done to exploit the drug delivery potential of such a polymeric stent. An antiproliferative drug (paclitaxel) was added either only to the top layer or to both layers and the in vitro release profiles were monitored for up to 90 days. Within 90 days, the measured paclitaxel release was almost entirely from the P(DL)LGA layer. In general, the release profiles show three distinct stages: (a) extremely slow diffusional release, (b) accelerated diffusion-degradation release, and (c) saturation. Separate degradation studies (water absorption, molecular weight reduction, weight loss, and surface topography) were also conducted to better understand the observed release behavior.

Biologically Active Core/shell Nanoparticles Self-assembled from Cholesterol-terminated PEG-TAT for Drug Delivery Across the Blood-brain Barrier

Biomaterials. Apr, 2008  |  Pubmed ID: 18155137

Biologically active polymer core/shell nanoparticles (i.e. micelles) self-assembled from TAT-poly(ethylene glycol) (PEG)-b-cholesterol (TAT-PEG-b-Chol) were fabricated and used as carrier for targeted blood-brain barrier delivery of antibiotics. Ciprofloxacin as a model antibiotic was efficiently loaded into the nanoparticles by a membrane dialysis method. The actual loading level of ciprofloxacin was dependent on initial loading of ciprofloxacin and fabrication temperature. The blank and ciprofloxacin-loaded nanoparticles were characterized using dynamic light scattering and SEM. The nanoparticles were spherical in nature, having an average size lower than 200 nm. The uptake of nanoparticles with TAT by human brain endothelial cells was greater than that of the nanoparticles without TAT. Most importantly, the nanoparticles with TAT were able to cross the blood-brain barrier (BBB), and located around the cell nucleus of neurons. These nanoparticles may provide a promising carrier to deliver antibiotics across the BBB for the treatment of brain infection.

Polymeric Micelles Anchored with TAT for Delivery of Antibiotics Across the Blood-brain Barrier

Biopolymers. 2008  |  Pubmed ID: 18412128

Polymeric micelles self-assembled from cholesterol-conjugated poly(ethylene glycol) (PEG) and anchored with transcriptional activator TAT peptide (TAT-PEG-b-Col) were fabricated for delivery of antibiotics across the blood-brain barrier (BBB). Ciprofloxacin, which demonstrated a high bactericidal effect, was efficiently loaded into the micelles by a membrane dialysis method. The ciprofloxacin-loaded micelles were characterized via dynamic light scattering and SEM. The micelles were spherical in nature, having an average diameter of smaller than 180 nm. Sustained release of ciprofloxacin was achieved over 6 h in phosphate-buffered saline (pH 7.4) at 37 degrees C. Confocal laser scanning microscopy reveals that the uptake of Fluorescein 5-isothiocyanate (FITC)-loaded TAT-PEG-b-Col micelles by human astrocytes was much higher than that of free FITC. Animal studies proved that these micelles crossed the BBB and entered the brain. The TAT-conjugated micelles may be used to deliver antibiotics across the BBB for treatment of brain infections.

Modeling of Drug Release from Biodegradable Polymer Blends

European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V. Nov, 2008  |  Pubmed ID: 18577449

Numerous mathematical models that predict drug release from degradable systems have been reported. Most of these models cater only to single step, diffusion-controlled release while a few attempt to describe bi-phasic release. All these models, however, are only applicable to drug release from single (unblended) degradable polymer systems. In this paper, we propose and test novel models for drug (notably paclitaxel) release from films made of neat poly (epsilon-caprolactone) PCL, neat poly (dl-lactide-co-glycolide) PLGA and their blends. The model developed for neat PCL consists of two terms: initial burst and diffusional release. On the other hand, a more complex model proposed for tri-phasic release from neat PLGA consists of burst release, degradative (relaxation-induced) drug dissolution release and diffusional release. Finally, this very first model to predict release from blend of PLGA and PCL was developed based on a heuristic approach. Drug distribution between PCL-rich and PLGA-rich phases is dictated by partition coefficient, and the overall fraction of drug release is a summation of drug released from the two phases. The proposed models exhibited good prediction of the experimental data.

Adjustable Paclitaxel Release Kinetics and Its Efficacy to Inhibit Smooth Muscle Cells Proliferation

Journal of Controlled Release : Official Journal of the Controlled Release Society. Aug, 2008  |  Pubmed ID: 18599145

Despite the success of drug-eluting stents in the field of interventional cardiology, very little work has been reported on the role of drug (paclitaxel) release kinetics on smooth muscle cell proliferation. This paper demonstrates how paclitaxel release from degradable polymers was successfully tailored from fast release rate to moderate and slow by changing the matrix composition. Cell counting and proliferation assays were employed to investigate the efficacy of each type of release kinetics in preventing human coronary artery smooth muscle cells proliferation. The fast release kinetics presented excellent inhibition immediately but may affect the re-endothelialization process. In this study, the moderate release kinetics appeared to be the best choice to prevent cell proliferation with consequently less effect on re-endothelialization. The slow release kinetics showed little inhibition in the early days but may be beneficial in the long term as a result of its sustained release.

A Novel Model and Experimental Analysis of Hydrophilic and Hydrophobic Agent Release from Biodegradable Polymers

Journal of Biomedical Materials Research. Part A. Sep, 2009  |  Pubmed ID: 18671269

Many factors affect the rate of drug release from biodegradable polymers. Here, we focus on investigating the effect of drug type on the degradation of P(DL)LGA 53/47 films and their ultimate release profiles. A freely water-soluble drug (metoclopramide monohydrochloride) exhibited an initial burst, whereas a water-insoluble drug (paclitaxel) exhibited an initial latent period with very little drug release. The onset of the second-stage release of the hydrophobic drug was delayed as compared with the hydrophilic drug. Overall, complete release of metoclopramide monohydrochloride was achieved much earlier than paclitaxel. In addition, the hydrophobic drug exhibited an extra stage of release when compared with the two-stage release for the hydrophilic drug. A novel model was developed to describe the underlying drug release mechanisms and kinetics. The model postulated that the total fraction of drug release from bulk-degrading polymer is a summation of three mechanisms: burst release, relaxation induced/drug-dissolution controlled release, and diffusional release. All the three steps are important for hydrophobic drugs. However, for hydrophilic drugs, burst and diffusional release steps are sufficient to account for the whole release process. The proposed model showed very good match with the experimental data.

Use of a Novel Anti-proliferative Compound Coated on a Biopolymer to Mitigate Platelet-derived Growth Factor-induced Proliferation in Human Aortic Smooth Muscle Cells: Comparison with Sirolimus

Glycoconjugate Journal. Aug, 2009  |  Pubmed ID: 18853254

Drug eluting stents (DES) have become a common mode of treatment for stenosis in coronary arteries. However, currently, the use of sirolimus/paclitaxel-coated DES has come under scrutiny, because of their pro-thrombotic effects leading to potential adverse outcomes in the long run. We have previously documented that D: -threo-1-phenyl-2-decanoylamino-3-morholino propanol (D-PDMP); an inhibitor of glucosylceramide synthase and lactosylceramide (LacCer) synthase markedly inhibited platelet-derived growth factor (PDGF)-induced cell proliferation. We have fabricated DES wherein, D-PDMP or sirolimus was coated on to a double layer of poly (lactic-co-glycolic acid) on a bare metal stent. The in vitro release of D-PDMP from biopolymer and its consequent effect on PDGF induced proliferation and apoptosis was assessed in human aortic smooth muscle cells (ASMC). D-PDMP was released from biopolymers in a dose-dependent fashion and was accompanied with a decrease in PDGF-induced cell proliferation, but not apoptosis. In contrast, sirolimus markedly increased apoptosis in these cells in addition to inhibiting proliferation. Our mechanistic studies revealed that D-PDMP, but not sirolimus decreased the cellular level of glucosyl and lactosylceramide that accompanied inhibition of PDGF-induced cell proliferation. Our short-term (14 days) in vivo studies in rabbits also attested to the safety and biocompatibility of the D-PDMP coated stents. Our data reveal the superiority of D-PDMP coated biopolymers over sirolimus coated biopolymers in mitigating ASMC proliferation. Such D-PDMP coated stents may be useful for localized delivery of drug to mitigate neo-vascular hyperplasia and other proliferative disorders.

A Novel Nanostructured Poly(lactic-co-glycolic-acid)-multi-walled Carbon Nanotube Composite for Blood-contacting Applications: Thrombogenicity Studies

Acta Biomaterialia. Nov, 2009  |  Pubmed ID: 19505600

Composite films of poly(lactic-co-glycolic-acid) with multi-walled carbon nanotubes (PLGA-MWCNT) having two different nanotube orientations, namely random and vertically aligned, have been fabricated and characterized. The effect of these nanostructured surfaces on platelet adhesion is evaluated. In particular, the thrombogenicity of the nanostructured composite films is compared with that of pristine graphite (a low thrombogenic material) and PLGA film, in order to determine the influence of surface chemistry and topography on platelet adhesion. The results in this study show that the PLGA-MWCNT composite with vertically aligned nanotubes exhibits very low levels of fibrinogen adsorption and platelet adhesion, which can be attributed to both chemical and topographical effects. Platelet adhesion shows a good correlation with the presence of COOH groups and appears to be sensitive to the topographic features of the composite films. The results in this study suggest that in addition to chemistry, nanotopographical surface modifications could be an effective strategy in the development of low thrombogenic and hemocompatible materials.

Self-assembled Cationic Peptide Nanoparticles As an Efficient Antimicrobial Agent

Nature Nanotechnology. Jul, 2009  |  Pubmed ID: 19581900

Antimicrobial cationic peptides are of interest because they can combat multi-drug-resistant microbes. Most peptides form alpha-helices or beta-sheet-like structures that can insert into and subsequently disintegrate negatively charged bacterial cell surfaces. Here, we show that a novel class of core-shell nanoparticles formed by self-assembly of an amphiphilic peptide have strong antimicrobial properties against a range of bacteria, yeasts and fungi. The nanoparticles show a high therapeutic index against Staphylococcus aureus infection in mice and are more potent than their unassembled peptide counterparts. Using Staphylococcus aureus-infected meningitis rabbits, we show that the nanoparticles can cross the blood-brain barrier and suppress bacterial growth in infected brains. Taken together, these nanoparticles are promising antimicrobial agents that can be used to treat brain infections and other infectious diseases.

The Short-term Effect on Restenosis and Thrombosis of a Cobalt-chromium Stent Eluting Two Drugs in a Porcine Coronary Artery Model

Journal of Interventional Cardiology. Oct, 2009  |  Pubmed ID: 19627432

The aim of this article was to study the effect of dual drug-eluting stent (DES) on both restenosis and thrombosis in a porcine coronary artery model. This study reports on the use of two drugs coated on the stent to simultaneously minimize both restenosis and thrombosis. The DES was prepared by spray coating a bare metal stent with a biodegradable polymer loaded with sirolimus and triflusal, to treat against restenosis and thrombosis, respectively. The two-layered dual drug-coated stent was characterized in vitro for surface properties before and after expansion, as well as for possible delamination by cross-sectioning the stent in vitro. In vivo animal studies (in a pig model) were then performed for acute thrombosis, inflammation, and restenosis. The results show a significant reduction in restenosis with a stent coated with both drugs compared with the controls (a bare metal stent, a sirolimus-coated, and a pure polymer-coated stent). The reduction in restenosis with a sirolimus/triflusal-eluting stent is associated with an inhibition of inflammation and thrombus formation, suggesting that such dual DES have a role to play for the treatment of coronary artery diseases.

The Effect of Topography of Polymer Surfaces on Platelet Adhesion

Biomaterials. Mar, 2010  |  Pubmed ID: 19945746

In this study, the effect of surface topography on fibrinogen and platelet adsorption was investigated. High aspect ratio surface features, in the submicron to nanometer range, were constructed on the poly- (lactic-co-glycolic-acid) (PLGA) films. The topographic surfaces were fabricated by solvent-mediated polymer casting on a master template. Fibrinogen adsorption and platelets adhesion on these topographic surfaces were quantified by enzyme linked immunosorbent assay (ELISA) and lactate dehydrogenase (LDH) assay respectively, while the activation of platelets was quantified by flow cytometric analysis using fluorescein isothiocyanate (FITC) tagging. The lowest fibrinogen adsorption amount and platelet activity was observed on surfaces with specific topographical features in the submicron range with a significant reduction in adhesion when compared to the pristine PLGA films. The topographical parameters found to induce low levels of fibrinogen adsorption and platelet response were high aspect ratio structures (>3:1) with reduced interspacing (<200 nm) or high density. The results signify that topographical manipulation of thrombogenic surfaces of biodegradable polymers is a feasible approach for reducing their thrombogenicity.

Aminosilane Micropatterns on Hydroxyl-terminated Substrates: Fabrication and Applications

Langmuir : the ACS Journal of Surfaces and Colloids. Apr, 2010  |  Pubmed ID: 19947614

The technique to pattern aminosilanes on hydroxyl-terminated substrates will open up extensive applications in many fields. There are some existing methods to pattern aminosilanes, in particular, (3-aminopropyl)triethoxysilane (APTES) on SiO(2) and glass substrates through indirect routes. However, few reports focus on the direct patterning of APTES by microcontact printing (microCP), due to the volatility of "inks" which consist of APTES and organic solvents. This report shows that high-quality APTES patterns on hydroxyl-terminated substrates can be directly obtained by microCP using an APTES aqueous solution as "ink". Gold nanoparticles (Au NPs) have been used to verify the presence and quality of APTES patterns on which they are selectively adsorbed. Thus-obtained Au NP patterns can serve as templates for the growth of ZnO nanostructures. Lectins are also successfully immobilized on the APTES patterns, with glutaraldehyde as linker. We believe that our method will serve as a general approach and find a wide range of applications in the fabrication of patterns and devices.

Immobilization of Recombinant Vault Nanoparticles on Solid Substrates

ACS Nano. Mar, 2010  |  Pubmed ID: 20146454

Native vaults are nanoscale particles found abundantly in the cytoplasm of most eukaryotic cells. They have a capsule-like structure with a thin shell surrounding a "hollow" interior compartment. Recombinant vault particles were found to self-assemble following expression of the major vault protein (MVP) in a baculovirus expression system, and these particles are virtually identical to native vaults. Such particles have been recently studied as potential delivery vehicles. In this study, we focus on immobilization of vault particles on a solid substrate, such as glass, as a first step to study their interactions with cells. To this end, we first engineered the recombinant vaults by fusing two different tags to the C-terminus of MVP, a 3 amino acid RGD peptide and a 12 amino acid RGD-strep-tag peptide. We have demonstrated two strategies for immobilizing vaults on solid substrates. The barrel-and-cap structure of vault particles was observed for the first time, by atomic force microscopy (AFM), in a dry condition. This work proved the feasibility of immobilizing vault nanoparticles on a material surface, and the possibility of using vault nanoparticles as localized and sustainable drug carriers as well as a biocompatible surface moiety.

In Vitro and in Vivo Performance of a Dual Drug-eluting Stent (DDES)

Biomaterials. May, 2010  |  Pubmed ID: 20189244

This study reports on a dual drug-eluting stent (DDES) that has an anti-proliferative and an anti-thrombotic in a biodegradable polymer-coated onto a cobalt-chromium stent. The DDES was prepared by spray coating the bare metal stent with a biodegradable polymer loaded with sirolimus and triflusal, to treat against restenosis and thrombosis, respectively. The 2-layered dual-drug coated stent was characterized in vitro for surface properties before and after expansion, as well as for possible delamination by cross-sectioning the stent in vitro. The in vitro anti-platelet behavior of the triflusal-loaded films was investigated by using dynamic platelet adhesion measurements. Additionally, the in vitro degradation and release study of the films and the stents w/single sirolimus and dual sirolimus-triflusal in different formulations were examined. Finally, in vivo studies (in a porcine carotid artery model) were performed for acute thrombosis, inflammation and restenosis at 30 days. The in vitro results show DDES can sustain release both anti-proliferation drug (sirolimus) and anti-thrombosis drug (triflusal), two drugs were controlled in different rates to effectively reduce thrombosis and proliferation at the same time. In vivo results show a significant reduction in restenosis with dual-drug eluting stent compared with the controls (a bare metal stent, a sirolimus coated and a pure polymer-coated stent). The reduction in restenosis with a dual sirolimus-triflusal eluting stent is associated with an inhibition of inflammation, especially thrombus formation, suggesting that such dual-drug eluting stents have a role to play for the treatment of coronary artery disease.

Optimizing Partition-controlled Drug Release from Electrospun Core-shell Fibers

International Journal of Pharmaceutics. Jun, 2010  |  Pubmed ID: 20227472

Controlled release of hydrophilic entities, such as peptides, proteins and even pDNA, is difficult to accomplish with conventional approaches. This work suggests one possible approach for controlled release of such actives using electrospun core-shell fiber structures. In particular, we propose strategies for partition control of the release. The fibers consist of two layers, with the outer polymer sleeve serving containing the inner core, in which the drug is encapsulated. By varying the physical and chemical properties of the core and shell solutions, we have shown that the release rate of a hydrophilic drug, metoclopramide hydrochloride, is controllable. Experimental results show a clear difference in the release pattern between monolithic fibers made of hydrophilic and hydrophobic polymers and various core-shell fibers with PCL, PLLA and PLGA 80/20 as shell polymers. The study yields insight into when partition control of release can be achieved in core-shell fibers, and with that, options for controlled release systems for hydrophilic drugs, peptides and pDNA.

Polymer- and Liposome-based Nanoparticles in Targeted Drug Delivery

Frontiers in Bioscience (Scholar Edition). Jun, 2010  |  Pubmed ID: 20515826

This review focuses on polymer- and liposome-based nanoparticles used in targeted delivery of bioactive molecules, from drugs to siRNA to pDNA. The perspective centers around commercial and clinical successes, and a rationalization of these successes. Microparticulate systems are not covered, and only those applications that truly utilize the advantages of nano size are covered. "Stealth" systems dominate in this review, as most of the clinical successes are for passive targeting rather than for active targeting of tissue. The relevance of nano size to gene delivery is also discussed with relevant examples.

Thermoplastic Biodegradable Elastomers Based on ε-caprolactone and L-lactide Block Co-polymers: a New Synthetic Approach

Acta Biomaterialia. Nov, 2010  |  Pubmed ID: 20566308

Although biodegradable polymers have found extensive application in medical devices, there are very few commercially available elastomeric biodegradable polymers. In this work, starting with the well-known monomers L-lactide and ε-caprolactone, we developed elastomers using a multiblock co-polymer approach. This ensures that the degradation products of such elastomers are also acceptable from a cytotoxicity standpoint. A series of polymers with various structures was synthesized utilizing a design of experiment approach. The basic structure is that of a diblock, with each block being modified by the addition of co-monomer. The synthesized polymers exhibited a range of mechanical properties from a typical thermoplastic polymer to that approaching a good thermoplastic elastomer. 13C nuclear magnetic resonance analysis, size exclusion chromatography and differential scanning calorimetry measurements have been utilized to relate the observed range of mechanical properties to the structure. In addition, the elastomeric nature has been established with the use of creep and recovery measurements. Such elastomers may find a variety of biomedical applications, ranging from stent coatings to atrial septal defect occluders.

Conformational Behavior of Fibrinogen on Topographically Modified Polymer Surfaces

Physical Chemistry Chemical Physics : PCCP. Sep, 2010  |  Pubmed ID: 20571633

The influence of topographical surface features at the submicron scale on the structural changes in the surface-adsorbed fibrinogen was investigated on poly(lactic-co-glycolic-acid) (PLGA) films. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) was employed in this study for the induced conformational change of fibrinogen over various adsorption times, while the adsorption kinetics of fibrinogen was quantified by the enzyme linked immunosorbent assay (ELISA). When a PLGA surface is modified topographically, the adsorbed fibrinogen undergoes less conformational change when compared to adsorption on the pristine PLGA surface. The extent of conformational change is related to platelet adhesion. Reduced thrombogenicity was demonstrated by the higher ratios of alpha-helix to beta-turn and beta-sheet to beta-turn structures on the topographic PLGA film, which suggests that topographical manipulation of surfaces is a viable approach to influence the thrombogenicity of surfaces.

Fully Biodegradable Septal Defect Occluder-a Double Umbrella Design

Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. Nov, 2010  |  Pubmed ID: 20976753

Current percutaneous devices for septal defect treatment are made of nondegradable metallic and synthetic fabric materials. These devices are not ideal due to risks of future complications from device erosions and potential obstructed access for future transseptal procedures. The biodegradable double umbrella device was made of fully biodegradable polymers, featured with two discs connected with a stretchable stem. The devices were inserted across the PFO model created on Yorkshire swines through a short sheath by open thoracotomy. Fluoroscopic imaging and echocardiography obtained during the 1-month follow-up study period showed that the devices were in stable position with no shunt. The in-vitro degradation study and post-mortem explantation confirmed that the devices have good integrity and mechanical strength during the 1-month trial. Furthermore, the devices appeared to be well endothelialized after 1 month. These results showed clearly that it is feasible to replace the current nondegradable devices with the new generation biodegradable PFO occluders. This work studied and proved the feasibility of interventional closure of patent foramen ovale (PFO) with a fully biodegradable device, that we call the "double umbrella" (DU) for its symbolic design. © 2010 Wiley-Liss, Inc.

Surface Modification of Poly(L-lactic Acid) with Biomolecules to Promote Endothelialization

Biointerphases. Sep, 2010  |  Pubmed ID: 21171711

Rapid endothelialization is important for biodegradable blood-contacting devices not only to prevent thrombosis but also to prevent degradation debris from entering the bloodstream and causing further complications. Here the authors report a three-step surface modification method, by which biomolecules, such as gelatin and chitosan, are covalently immobilized on the surface of plasma-treated poly(L-lactic acid) (PLLA) via -COOH groups introduced by acrylic acid grafting polymerization. Surface characterization techniques, including x-ray photoelectron spectroscopy, contact angle measurement, and colorimetric methods for surface density of functional groups, proved the feasibility and stability of this surface modification method. Surface wettability was increased by biomolecules immobilization. The -COOH surface density was measured to be 4.17±0.15 μmol/cm(2), the and amount of gelatin immobilized was 4.8 μg/cm(2). Human umbilical vein endothelial cell was used during in vitro study at seeding density of 10(4) cells/cm(2). PLLA-gAA-gelatin surface was found to enhance cell adhesion, spreading, focal adhesion formation, and proliferation significantly. Chitosan-modified PLLA shows marginally improvement in cell adhesion and proliferation. Endothelialization was achieved within 7 days on both modified PLLA surfaces. In conclusion, this work demonstrates the feasibility of the surface modification method, and its ability to promote complete endothelialization for cardiovascular applications.

Adhesion, Proliferation, and Gene Expression Profile of Human Umbilical Vein Endothelial Cells Cultured on Bilayered Polyelectrolyte Coatings Composed of Glycosaminoglycans

Biointerphases. Sep, 2010  |  Pubmed ID: 21171714

This study characterized human umbilical vein endothelial cell (HUVEC) adhesion, proliferation, and gene expression on bilayered polyelectrolyte coatings composed of an outermost layer of glycosaminoglycans (hyaluronan, heparin, or chondroitin sulfate), with an underlying layer of poly-L-lysine or chitosan. The proportion of cells that adhered to the various polyelectrolyte coatings after 1 and 2 h incubations was quantified by the WST-8 assay. Interchanging poly-L-lysine with chitosan resulted in significant differences in cellular adhesion to the outermost glycosaminoglycan layer after 1 h, but these differences became insignificant after 2 h. The proliferation of HUVEC on the various bilayered polyelectrolyte coatings over 10 days was characterized using the WST-8 assay. Regardless of whether the underlying layer was poly-L-lysine or chitosan, HUVEC proliferation on the hyaluronan outermost layer was significantly less than on heparin or chondroitin sulfate. Additionally, it was observed that there was more proliferation with poly-L-lysine as the underlying layer, compared to chitosan. Subsequently, real-time polymerase chain reaction was used to analyze the expression of seven genes related to adhesion, migration, and endothelial function (VWF, VEGFR, VEGFA, endoglin, integrin-α5, ICAM1, and ICAM2) by HUVEC cultured on the various bilayered polyelectrolyte coatings for 3 days. With poly-L-lysine as the underlying layer, biologically significant differences (greater than twofold) in the expression of VWF, VEGFR, VEGFA, endoglin, and ICAM1 were observed among the three glycosaminoglycans. With chitosan as the underlying layer, all three glycosaminoglycans displayed biologically significant differences in the expression of VWF and VEGFR compared to the chitosan control. CT-HA displayed the highest level of expression of VWF, whereas expression levels of VEGFR were almost similar among the three glycosaminoglycans.

Sustained Release of Complexed DNA from Films: Study of Bioactivity and Intracellular Tracking

Biointerphases. Sep, 2010  |  Pubmed ID: 21171716

Sustained DNA delivery from polymeric films provides a means for localized and prolonged gene therapy. However, in the case of bioactive molecules such as plasmid DNA (pDNA), there are limitations on the achievable release profiles as well as on the maintenance of bioactivity over time. In this report, the authors have investigated the bioactivity of the released DNA (naked and complexed with lipofectamine) from polymeric films using in vitro cell transfection of COS-7 cell lines. The polymeric system consists of a biodegradable semicrystalline polymer such as poly(ε-caprolactone) (PCL) with or without blended gelatin. Sustained release of lipoplexes and of pDNA is shown over several days. However, lipoplexes released from pure PCL films show no transfection on day 18, whereas lipoplexes released from PCL-gelatin films continue to transfect cells on day 18 of release. Confocal studies were used to determine the reasons for this difference in transfection efficiency, and it is proposed that association of the lipoplex with gelatin confers protection from degradation in the cytoplasm. The results also showed that the bioactivity of released lipoplexes was superior to that of the naked pDNA. For both naked pDNA and the lipoplexes, the presence of gelatin helped to maintain the bioactivity over several days.

Effect of Cell-seeding Density on the Proliferation and Gene Expression Profile of Human Umbilical Vein Endothelial Cells Within Ex Vivo Culture

Cytotherapy. May, 2011  |  Pubmed ID: 21171823

Characterization of endothelial cell-biomaterial interaction is crucial for the development of blood-contacting biomedical devices and implants. However, a crucial parameter that has largely been overlooked is the cell-seeding density.

Modeling of Drug Release from Bulk-degrading Polymers

International Journal of Pharmaceutics. Oct, 2011  |  Pubmed ID: 21182912

This paper aims to provide a comprehensive review of the various models or simulations for predicting drug release from bulk-degrading systems. A brief description of bulk degradation processes and factors affecting the degradation rate, and consequently the release kinetics, is presented first. Next, several important classical models, often used as the basis for subsequent model development, are discussed. Both mathematical models and Monte-Carlo based simulations have been developed for controlled release from bulk-degrading systems. The mathematical models can be further subdivided into two categories. First, the diffusion-based models whose transport mechanism is mainly governed by diffusion, but with degradation-dependent diffusion coefficients. These are generally simpler and easier to use and are sufficient to illustrate mono-phasic release. Second, comprehensive models that combine diffusion with other theories such as erosion, drug dissolution and/or pore percolations. These models usually involve more complex equations but provide good matches for multi-phasic release profiles.

Nanoscale-controlled Enzymatic Degradation of Poly(L-lactic Acid) Films Using Dip-pen Nanolithography

Small (Weinheim an Der Bergstrasse, Germany). Jan, 2011  |  Pubmed ID: 21213386

Seeding Density Matters: Extensive Intercellular Contact Masks the Surface Dependence of Endothelial Cell-biomaterial Interactions

Journal of Materials Science. Materials in Medicine. Feb, 2011  |  Pubmed ID: 21221736

The effects of seeding density have often been overlooked in evaluating endothelial cell-biomaterial interactions. This study compared the cell attachment and proliferation characteristics of endothelial cells on modified poly (L: -lactic acid) (PLLA) films conjugated to gelatin and chitosan at low and high seeding densities (5,000 and 50,000 cells/cm(2)). During the early stage (2 h) of cell-biomaterial interaction, a low seeding density enabled us to observe the intrinsic surface-dependent differences in cell attachment capacity and morphogenesis, whereas extensive intercellular interactions at high seeding density masked differences between substrates and improved cell attachment on low-affinity substrates. During the later stage of cell-biomaterial interaction over 7-days of culture, the proliferation rate was found to be surface-dependent at low seeding density, whereas this surface-dependent difference was not apparent at high seeding density. It is recommended that low seeding density should be utilized for evaluating biomaterial applications where EC density is likely to be low, such as in situ endothelialization of blood-contacting devices.

The Effect of Polyethylene Glycol Structure on Paclitaxel Drug Release and Mechanical Properties of PLGA Thin Films

Acta Biomaterialia. May, 2011  |  Pubmed ID: 21300188

Thin films of poly(lactic acid-co-glycolic acid) (PLGA) incorporating paclitaxel typically have slow release rates of paclitaxel of the order of 1 μg day(-1) cm(-2). For implementation as medical devices a range of zero order release rates (i.e. 1-15 μg day(-1) cm(-2)) is desirable for different tissues and pathologies. Eight and 35 kDa molecular weight polyethylene glycol (PEG) was incorporated at 15%, 25% and 50% weight ratios into PLGA containing 10 wt.% paclitaxel. The mechanical properties were assessed for potential use as medical implants and the rates of release of paclitaxel were quantified as per cent release and the more clinically useful rate of release in μg day(-1) cm(-2). Paclitaxel quantitation was correlated with the release of PEG from PLGA, to further understand its role in paclitaxel/PLGA release modulation. PEG release was found to correlate with paclitaxel release and the level of crystallinity of the PEG in the PLGA film, as measured by Raman spectrometry. This supports the concept of using a phase separating, partitioning compound to increase the release rates of hydrophobic drugs such as paclitaxel from PLGA films, where paclitaxel is normally homogeneously distributed/dissolved. Two formulations are promising for medical device thin films, when optimized for tensile strength, elongation, and drug release. For slow rates of paclitaxel release an average of 3.8 μg day(-1) cm(-2) using 15% 35k PEG for >30 days was achieved, while a high rate of drug release of 12 μg day(-1) cm(-2) was maintained using 25% 8 kDa PEG for up to 12 days.

High-throughput Screening of PLGA Thin Films Utilizing Hydrophobic Fluorescent Dyes for Hydrophobic Drug Compounds

Journal of Pharmaceutical Sciences. Oct, 2011  |  Pubmed ID: 21607953

Hydrophobic, antirestenotic drugs such as paclitaxel (PCTX) and rapamycin are often incorporated into thin film coatings for local delivery using implantable medical devices and polymers such as drug-eluting stents and balloons. Selecting the optimum coating formulation through screening the release profile of these drugs in thin films is time consuming and labor intensive. We describe here a high-throughput assay utilizing three model hydrophobic fluorescent compounds: fluorescein diacetate (FDAc), coumarin-6, and rhodamine 6G that were incorporated into poly(d,l-lactide-co-glycolide) (PLGA) and PLGA-polyethylene glycol films. Raman microscopy determined the hydrophobic fluorescent dye distribution within the PLGA thin films in comparison with that of PCTX. Their subsequent release was screened in a high-throughput assay and directly compared with HPLC quantification of PCTX release. It was observed that PCTX controlled-release kinetics could be mimicked by a hydrophobic dye that had similar octanol-water partition coefficient values and homogeneous dissolution in a PLGA matrix as the drug. In particular, FDAc was found to be the optimal hydrophobic dye at modeling the burst release as well as the total amount of PCTX released over a period of 30 days.

Layer-by-layer Microcapsules Templated on Erythrocyte Ghost Carriers

International Journal of Pharmaceutics. Aug, 2011  |  Pubmed ID: 21699968

This work reports the fabrication of layer-by-layer (LbL) microcapsules that provide a simple mean for controlling the burst and subsequent release of bioactive agents. Red blood cell (RBC) ghosts were loaded with fluorescently labeled dextran and lysozyme as model compounds via hypotonic dialysis with an encapsulation efficiency of 27-31%. It is demonstrated that these vesicles maintain their shape and integrity and that a uniform distribution of the encapsulated agents within these carriers is achieved. The loaded vesicles were then successfully coated with the biocompatible polyelectrolytes, poly-L-arginine hydrochloride and dextran sulfate. It is demonstrated that the release profiles of the encapsulated molecules can be regulated over a wide range by adjusting the number of polyelectrolyte layers. In addition, the LbL shell also protects the RBC ghost from decomposition thereby potentially preserving the bioactivity of encapsulated drugs or proteins. These microcapsules, consisting of an RBC ghost coated with a polyelectrolyte multilayer, provide a simple mean for the preparation of loaded LbL microcapsules eliminating the core dissolution and post-loading of bioactive agents, which are required for conventional LbL microcapsules.

Triblock Copolymers of ε-caprolactone, L-lactide, and Trimethylene Carbonate: Biodegradability and Elastomeric Behavior

Journal of Biomedical Materials Research. Part A. Oct, 2011  |  Pubmed ID: 21793195

For the triblock copolymer of ε-caprolactone, trimethylene carbonate, and L-lactide, where L-lactide blocks form the two ends, there is a range of compositions over which elastomeric behavior is obtained. Within this composition range, these polymers show good creep and recovery at ambient temperature, and exhibit high elongations to break. Additionally, we demonstrate that the recovery is independent of stress and strain for the elastomer compositions. The range of compositions that yield elastomeric character is rationalized based on the structure; specifically, there must be a minimum crystallinity of the end blocks and no crystallinity in the midblock, in addition to molar mass requirements. These polymers degrade by simple hydrolysis, and the rate of degradation is potentially programmable by manipulation of the molar ratio of hard segment to soft segment. Compared to biodegradable polyurethane, these polymers are expected to yield less harmful degradation products, and offer more variables for manipulation of properties. These polymers are also processable from the melt at temperatures exceeding about 130 °C. We expect to use these polymers in a variety of applications, including stent coatings, fully-degradable stents, and atrial septal defect occluders.

Biocompatibility and Biodegradation Studies of Subconjunctival Implants in Rabbit Eyes

PloS One. 2011  |  Pubmed ID: 21799878

Sustained ocular drug delivery is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Biodegradable subconjunctival implants with controlled drug release may circumvent these two problems. In our study, two microfilms (poly [d,l-lactide-co-glycolide] PLGA and poly[d,l-lactide-co-caprolactone] PLC were developed and evaluated for their degradation behavior in vitro and in vivo. We also evaluated the biocompatibility of both microfilms. Eighteen eyes (9 rabbits) were surgically implanted with one type of microfilm in each eye. Serial anterior-segment optical coherence tomography (AS-OCT) scans together with serial slit-lamp microscopy allowed us to measure thickness and cross-sectional area of the microfilms. In vitro studies revealed bulk degradation kinetics for both microfilms, while in vivo studies demonstrated surface erosion kinetics. Serial slit-lamp microscopy revealed no significant inflammation or vascularization in both types of implants (mean increase in vascularity grade PLGA50/50 12±0.5% vs. PLC70/30 15±0.6%; P = 0.91) over a period of 6 months. Histology, immunohistochemistry and immuno-fluorescence also revealed no significant inflammatory reaction from either of the microfilms, which confirmed that both microfilms are biocompatible. The duration of the drug delivery can be tailored by selecting the materials, which have different degradation kinetics, to suit the desired clinical therapeutic application.

A Novel Bioabsorbable Drug-eluting Tracheal Stent

The Laryngoscope. Oct, 2011  |  Pubmed ID: 21823127

Currently available silicone and metallic stents for tracheal stenosis are associated with problems of granulations, mucus trapping, and difficult removals. Our aim was to develop a novel bioabsorbable tracheal stent with mitomycin C (MMC) drug elution to circumvent such problems.

Single-layer Graphene Oxide Sheet: a Novel Substrate for Dip-pen Nanolithography

Chemical Communications (Cambridge, England). Sep, 2011  |  Pubmed ID: 21829792

Graphene oxide (GO) sheet is used as a novel substrate for dip-pen nanolithography (DPN). After GO is transferred onto SiO(2) using the Langmuir-Blodgett technique, CoCl(2) is patterned on both GO and exposed SiO(2) substrates simultaneously by DPN, which is used for growth of different structured carbon nanotubes.

Sustained Release of an Anti-glaucoma Drug: Demonstration of Efficacy of a Liposomal Formulation in the Rabbit Eye

PloS One. 2011  |  Pubmed ID: 21931735

Topical medication remains the first line treatment of glaucoma; however, sustained ocular drug delivery via topical administration is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Currently, daily topical administration for lowering the intra-ocular pressure (IOP), has many limitations, such as poor patient compliance and ocular allergy from repeated drug administration. Poor compliance leads to suboptimal control of IOP and disease progression with eventual blindness. The delivery of drugs in a sustained manner could provide the patient with a more attractive alternative by providing optimal therapeutic dosing, with minimal local toxicity and inconvenience. To investigate this, we incorporated latanoprost into LUVs (large unilamellar vesicles) derived from the liposome of DPPC (di-palmitoyl-phosphatidyl-choline) by the film hydration technique. Relatively high amounts of drug could be incorporated into this vesicle, and the drug resides predominantly in the bilayer. Vesicle stability monitored by size measurement and DSC (differential scanning calorimetry) analysis showed that formulations with a drug/lipid mole ratio of about 10% have good physical stability during storage and release. This formulation demonstrated sustained release of latanoprost in vitro, and then tested for efficacy in 23 rabbits. Subconjunctival injection and topical eye drop administration of the latanoprost/liposomal formulation were compared with conventional daily administration of latanoprost eye drops. The IOP lowering effect with a single subconjunctival injection was shown to be sustained for up to 50 days, and the extent of IOP lowering was comparable to daily eye drop administration. Toxicity and localized inflammation were not observed in any treatment groups. We believe that this is the first demonstration, in vivo, of sustained delivery to the anterior segment of the eye that is safe and efficacious for 50 days.

Evaluation of Sustained Release of PLC-loaded Prednisolone Acetate Microfilm on Postoperative Inflammation in an Experimental Model of Glaucoma Filtration Surgery

Current Eye Research. Dec, 2011  |  Pubmed ID: 22007761

To evaluate the effect of a biodegradable microfilm with sustained release of prednisolone acetate (PA) on postoperative wound healing after experimental glaucoma filtration surgery (GFS).

A New Insight for an Old System: Protein-PEG Colocalization in Relation to Protein Release from PCL/PEG Blends

Molecular Pharmaceutics. Dec, 2011  |  Pubmed ID: 22034836

Quantification of protein-polymer colocalization in a phase-separated polymer blend gives important insights into the protein release mechanism. Here, we report on the first visualization of protein-poly(ethylene glycol) (protein-PEG) colocalization in poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) blend films using a combined application of confocal Raman mapping and confocal laser scanning microscopy (CLSM) imaging. The degree of protein-PEG colocalization was further quantified via a novel image processing technique. This technique also allowed us to characterize the 3-D protein distribution within the films. Our results showed that the proteins were homogeneously distributed within the film matrix, independent of PEG content. However, the degree of protein-PEG colocalization was inversely proportional to PEG content, ranging from 65 to 94%. This quantitative data on protein-PEG colocalization was used along with in vitro PEG leaching profile to construct a predictive model for overall protein release. Our prediction matched well with the experimental protein release profile, which is characterized by an initial burst release and a subsequent slower diffusional release. More importantly, the success of this predictive model has highlighted the influence of protein-PEG colocalization on the protein release mechanism.

A Novel Biodegradable Septal Defect Occluder: the "Chinese Lantern" Design, Proof of Concept

Innovations (Philadelphia, Pa.). Jul, 2011  |  Pubmed ID: 22437979

Atrial septal defect (ASD) is a general term used to describe an opening in the atrial septum that divides the two atria; unless the hole is occluded, it can give rise to serious complications. Given the need for percutaneous deployment for ASD or patent foramen ovale (PFO) occluders, all currently available devices are made of metals (specifically nitinol) and synthetic fabric. However, their permanent presence in the human body is not desirable due to the risks of long-term allergy, toxicity, and complications such as thrombus formation, device arm fracture, and nickel allergy. Once the hole is covered by a newly regenerated tissue, the device is no longer needed; thus it is ideal if the device is fully absorbed by the body when healing is completed.

Effect of Polymer Type on the Dynamics of Phase Inversion and Drug Release in Injectable in Situ Gelling Systems

Journal of Biomaterials Science. Polymer Edition. 2012  |  Pubmed ID: 21244721

The objective of this study was to evaluate the effect of the nature of the polymer on the dynamics of phase inversion and drug release in an in situ forming gel drug-delivery system composed of a biodegradable polymer and the solvent N-methyl-2-pyrrolidone (NMP), with metoclopramide monohydrochloride (metosalt) used as a low-molecular-weight model drug. Injection of this solution into an aqueous medium leads to the formation of a solid gel due to the rapid solvent/water exchange, followed by sustained release of the incorporated drug. The release of solvent from the injectable gel into phosphate buffer, which influences the polymer precipitation rate, was investigated as a function of the type of polymer using UV-Vis spectrophotometry. The cross-sectional gel morphology and its water uptake were characterized to relate the initial burst release (and thus the dynamics of phase inversion) to the polymer lactide/glycolide ratio and to the end-group characteristics. The results show that the phase inversion of hydrophobic polymers (e.g., PdlLA) occurs faster than the phase inversion of relatively more hydrophilic polymers (e.g., PLGA75/25, RG502 and RG502H). Three of the four polymers exhibit a four-phase profile, with the characteristics of each phase dependent on the hydrophobicity and degradation kinetics of the individual polymer.

Engineering of Erythrocyte-based Drug Carriers: Control of Protein Release and Bioactivity

Journal of Materials Science. Materials in Medicine. Jan, 2012  |  Pubmed ID: 22095447

This work reports the fabrication of layer-by-layer (LbL) polyelectrolyte coated erythrocyte carriers that provide a simple means for controlling the burst and subsequent release of lysozyme. Erythrocytes were loaded with RITC-lysozyme as model compound via the hypotonic dialysis method. An encapsulation efficiency of 41.6% and a loading amount of 12.7 pg/cell was achieved. It is demonstrated that these carriers maintain their shape and integrity similar to natural erythrocytes after the encapsulation procedures, and achieve a uniform distribution of the encapsulated lysozyme. The erythrocyte carriers were fixed with glutaraldehyde and then successfully coated with biocompatible polyelectrolytes, poly-L: -lysine hydrobromide and dextran sulfate, using the LbL method. It is demonstrated that the release profile of the encapsulated macromolecule can be regulated by adjusting the number of polyelectrolyte layers. Furthermore by adjusting the concentrations of the cross linking agent the activity of the encapsulated lysozyme can be well preserved. These core-shell microcapsules, consisting of erythrocytes loaded with bioactive substances and coated with a polyelectrolyte multilayer shell, hold promise for a new type of biocompatible and biodegradable drug delivery system.

A Fully Degradable Tracheal Stent: in Vitro and in Vivo Characterization of Material Degradation

Journal of Biomedical Materials Research. Part B, Applied Biomaterials. Apr, 2012  |  Pubmed ID: 22121065

We report on the testing of materials for a fully degradable tracheal stent. Such a stent has several advantages over currently used permanent stents made of metal or silicone polymers. However, the mode of degradation in the trachea is expected to be different from a fully submerged device, because of the uniqueness of the tracheal environment. A physical model was developed to allow an in-depth study of degradation of bioabsorbable polymers exposed to two differing media; namely 70 wt % water (gel) on one side and humidified air on the other, simulating conditions in a tracheal passage. Longitudinal microtome slices were obtained from both polymer surfaces and degradation kinetics data were derived from size exclusion chromatography. On the basis of the data obtained, it is observed that well-studied bulk-degrading polymers might show surface-eroding properties in such an environment. Generally, hydrophobic polymers retard the formation of a water concentration gradient and exhibit bulk-degradation kinetics. However, addition of specific plasticizers can influence the water uptake gradient, and force the polymer towards a pseudo "surface-eroding" behavior. In vivo studies in a rabbit model of degradable stents made from a selected polymer, demonstrate the feasibility of a fully bioabsorbable tracheal stent. This study aims to improve understanding of degradation of polymers under heterogeneous environments.

Nanomedicine for Glaucoma: Liposomes Provide Sustained Release of Latanoprost in the Eye

International Journal of Nanomedicine. 2012  |  Pubmed ID: 22275828

To report the development and therapeutic evaluation of a liposomal nanocarrier for sustained release of latanoprost, in the rabbit eye.

Surface Modification of Smooth Poly(L-lactic Acid) Films for Gelatin Immobilization

ACS Applied Materials & Interfaces. Feb, 2012  |  Pubmed ID: 22276668

Poly(L-lactic acid) (PLLA) is widely used in drug delivery and medical implants. Surface modification of PLLA with functional groups to immobilize gelatin or other extracellular matrix proteins is commonly used to improve its cellular affinity. In this work, we use the oxygen plasma to treat PLLA film followed by modification with organosilanes with different functional groups, such as amine, epoxy, and aldehyde groups. Gelatin is then immobilized on the modified PLLA film, which is confirmed by water contact angle measurement, atomic force microscopy (AFM), and laser scanning confocal microscopy (LSCM). Among the used organosilanes, aminosilane is the best one for modification of PLLA used for immobilization of gelatin with the highest efficiency. Moreover, the cellular affinity of gelatin-immobilized PLLA is studied through the evaluation of cell proliferation and focal adhesion using the human umbilical vein endothelial cells (HUVECs). Our experimental results show that the gelatin immobilized on aminosilane- and aldehyde-silane-modified PLLA improves the cellular affinity of HUVECs, whereas that immobilized on epoxy-silane-modified PLLA does not show significant improvement on the cell proliferation.

Novel Gradient Casting Method Provides High-throughput Assessment of Blended Polyester Poly(lactic-co-glycolic Acid) Thin Films for Parameter Optimization

Acta Biomaterialia. Jul, 2012  |  Pubmed ID: 22293582

Pure polymer films cannot meet the diverse range of controlled release and material properties demanded for the fabrication of medical implants or other devices. Additives are added to modulate and optimize thin films for the desired qualities. To characterize the property trends that depend on additive concentration, an assay was designed which involved casting a single polyester poly(lactic-co-glycolic acid) (PLGA) film that blends a linear gradient of any PLGA-soluble additive desired. Four gradient PLGA films were produced by blending polyethylene glycol or the more hydrophobic polypropylene glycol. The films were made using a custom glass gradient maker in conjunction with a 180 cm film applicator. These films were characterized in terms of thickness, percent additive, total polymer (PLGA+additive), and controlled drug release using drug-like fluorescent molecules such as coumarin 6 (COU) or fluorescein diacetate (FDAc). Material properties of elongation and modulus were also accessed. Linear gradients of additives were readily generated, with phase separation being the limiting factor. Additive concentration had a Pearson's correlation factor (R) of >0.93 with respect to the per cent total release after 30 days for all gradients characterized. Release of COU had a near zero-order release over the same time period, suggesting that coumarin analogs may be suitable for use in PLGA/polyethylene glycol or PLGA/polypropylene glycol matrices, with each having unique material properties while allowing tuneable drug release. The gradient casting method described has considerable potential in offering higher throughput for optimizing film or coating material properties for medical implants or other devices.

Triblock Copolymers of ε-caprolactone, Trimethylene Carbonate, and L-lactide: Effects of Using Random Copolymer As Hard-block

Journal of the Mechanical Behavior of Biomedical Materials. Feb, 2012  |  Pubmed ID: 22301176

A series of triblock copolymers comprising end block of PLLA modified with PCL, and random copolymer of PCL and PTMC as soft segment were synthesized. DSC data show that PCL disrupted the crystallinity of PLLA, making the hard block to be completely amorphous when the PCL content is 50%. Correspondingly, the addition of PCL into PLLA block enhances the elongation of the triblock considerably. With regards to the elasticity, however, creep test results show that adding PCL to PLLA block seems to reduce the "equilibrium" recovery, while cyclic test results shows that the instantaneous recovery increased significantly with more PCL inside PLLA block. It was also observed that the degradation rate of triblock with added PCL inside the PLLA was slower compared to triblock with pure PLLA hard block. Compared to biodegradable polyurethane, these polymers are expected to yield less harmful degradation products, and offer more variables for the manipulation of properties. These polymers are also processable from the melt at temperatures exceeding about 130 °C. We expect to use these polymers in a variety of applications, including stent coatings, fully-degradable stents and atrial septal defect occluders.

Cosolvent Effects on the Drug Release and Depot Swelling in Injectable in Situ Depot-forming Systems

Journal of Pharmaceutical Sciences. May, 2012  |  Pubmed ID: 22318766

Although injectable depot-forming solutions have been commercialized, the factors that influence the overall release kinetics from such systems are still not fully understood. In this work, we address the effect of cosolvent on the issue of excessive burst release of potent bioactives from injectable depot-forming solutions. Specifically, we have evaluated the influence of addition of a relatively hydrophobic cosolvent (triacetin) to more hydrophilic biocompatible solvents such as dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP) on the burst release. Drug release and solvent release results demonstrate that high burst release that occurred when only hydrophilic solvent was used as solvent was significantly reduced by adding triacetin as a cosolvent. The profiles of drug release were in good agreement with the profiles of the hydrophilic solvent DMSO or NMP release, and the suppression of the burst by triacetin addition is due to the suppression of the solvent release. Surprisingly, the swelling of the depot increased with triacetin amount and the depot morphology became more porous compared with the absence of triacetin. Usage of hydrophobic solvent as a cosolvent to reduce the burst release was shown to be more effective on the hydrophobic PdlLA depot and less effective on the relatively hydrophilic RG502 depot.

Synthesis and Antitumor Activity of Lapathoside D and Its Analogs

European Journal of Medicinal Chemistry. Jul, 2012  |  Pubmed ID: 22542106

Phenylpropanoid sucrose esters are important class of plant-derived natural products and have greater potential to be leads for new drugs because of their structural diversity and broad-array of pharmacological and biological activities. Regio- and chemo-selective acylation of 2,1':4,6-O-di-isopropylidene sucrose 4 with cinnamoyl chloride 5 and p-acetoxycinnamoyl chloride 6 afforded mono-, di-, tri- and tetra- variant PSEs in moderate yields. The first total synthesis of di-substituted PSE, lapathoside D 1' has been achieved successfully in short and simple synthetic steps from sucrose 3 as an inexpensive starting material. Lapathoside D 1 and a set of selected synthesized PSEs were tested for in vitro cytotoxicity against human cervical epithelioid carcinoma (HeLa) cell lines. Most of the compounds exhibited significant antitumor activity with their IC(50) values ranging from 0.05 to 7.63 μM. The primary screening results indicated that PSEs might be valuable source for new potent anticancer drug candidates.

Thick Acellular Heart Extracellular Matrix with Inherent Vasculature: a Potential Platform for Myocardial Tissue Regeneration

Tissue Engineering. Part A. Oct, 2012  |  Pubmed ID: 22663095

The decellularization of porcine heart tissue offers many opportunities for the production of physiologically relevant myocardial mimetic scaffolds. Earlier, we reported the successful isolation of a thin porcine cardiac extracellular matrix (pcECM) exhibiting relevant bio-mechanical properties for myocardial tissue engineering. Nevertheless, since native cardiac tissue is much thicker, such thin scaffolds may offer limited regeneration capacity. However, generation of thicker myocardial mimetic tissue constructs is hindered by diffusion limitations (~100 μm), and the lack of a proper vascular-like network within these constructs. In our present work, we focused on optimizing the decellularization procedure for thicker tissue slabs (10-15 mm), while retaining their inherent vasculature, and on characterizing the resulting pcECM. The trypsin/Triton-based perfusion procedure that resulted in a nonimmunogenic and cell-supportive pcECM was found to be more effective in cell removal and in the preservation of fiber morphology and structural characteristics than stirring, sonication, or sodium dodecyl sulfate/Triton-based procedures. Mass spectroscopy revealed that the pcECM is mainly composed of ECM proteins with no apparent cellular protein remains. Mechanical testing indicated that the obtained pcECM is viscoelastic in nature and possesses the typical stress-strain profile of biological materials. It is stiffer than native tissue yet exhibits matched mechanical properties in terms of energy dissipation, toughness, and ultimate stress behavior. Vascular network functionality was maintained to the first three-four branches from the main coronary vessels. Taken together, these results reaffirm the efficiency of the decellularization procedure reported herein for yielding thick nonimmunogenic cell-supportive pcECM scaffolds, preserving both native tissue ultra-structural properties and an inherent vascular network. When reseeded with the appropriate progenitor cells, these scaffolds can potentially serve as ex vivo screening platforms for new therapeutics, as models for human cardiac ECM, or as biomedical constructs for patch or transmural transplantation strategies.

Surface Functionalization of Nanoparticles to Control Cell Interactions and Drug Release

Small (Weinheim an Der Bergstrasse, Germany). Aug, 2012  |  Pubmed ID: 22674655

Nanoparticles made from poly(dl-lactide-co-glycolide) (PLGA) are used to deliver a wide range of bioactive molecules, due to their biocompatibility and biodegradability. This study investigates the surface modification of PLGA nanoparticles via the layer-by-layer (LbL) deposition of polyelectrolytes, and the effects of these coatings on the release behavior, cytotoxicity, hemolytic activity, and cellular uptake efficiency. PLGA nanoparticles are modified via LbL adsorption of two polyelectrolyte pairs: 1) poly(allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS) and 2) poly(L-lysine hydrobromide) (PLL) and dextran sulfate (DES). It is demonstrated that both PAH/PSS and PLL/DES coatings suppress the burst release usually observed for unmodified PLGA nanoparticles and that the release behavior can be adjusted by changing the layer numbers, layer materials, or by crosslinking the layer constituents. Neither bare nor polyelectrolyte-modified PLGA nanoparticles show any signs of cytotoxicity. However, nanoparticles with a positively charged polyelectrolyte as the outermost layer induce hemolysis, whereas uncoated particles or particles with a negatively charged polyelectrolyte as the outermost layer show no hemolytic activity. Furthermore, particles with either PAH or PLL as the outermost layer also demonstrate a higher uptake efficiency by L929 fibroblast cells, due to a higher cell-particle affinity. This study suggests that LbL coating of PLGA nanoparticles can control the release behavior of bioactive molecules as well as the surface activity, therefore providing a promising strategy to enhance the efficiency of nanoparticulate drug-delivery systems.

Characterization and Degradation of Elastomeric Four-armed Star Copolymers Based on Caprolactone and L-lactide

Journal of Biomedical Materials Research. Part A. Dec, 2012  |  Pubmed ID: 22807099

Although biodegradable polymers have found extensive applications in medical areas, there are limited reports that show elastomeric behavior. In this work, a biodegradable, elastomeric polymer is demonstrated from a four-armed star copolymer. With a fixed middle core composition, comprising caprolactone (CL) and L-lactide (LA), an elastomer is obtained by increasing the polylactide (PLA) end block lengths to obtain sufficient end block crystallinity. This increase suppressed the middle core's crystallinity yet ensured cocrystallization of the PLA ends of individual star copolymer chains to form a three-dimensional network via physical crosslinking. Cyclic and creep test of the star copolymers showed that at least 75% of recovery was achieved. Degradation study of the copolymer showed that degradation first occurred in the caprolactone-co-lactide (CLLA) core, followed by degradation in the PLA ends. Chain scission in the middle core resulted in immediate formation of CL crystals within the core and increased crystallinity over time, in both CLLA core and PLA ends.

Synthesis and Antiproliferative Activity of Helonioside A, 3',4',6'-tri-O-feruloylsucrose, Lapathoside C and Their Analogs

European Journal of Medicinal Chemistry. Dec, 2012  |  Pubmed ID: 23153813

The first total synthesis of natural phenylpropanoid sucrose esters (PSEs) helonioside A 1, 3',4',6'-tri-O-feruloylsucrose 2 and lapathoside C 3 along with 17 unnatural PSE analogs has been successfully accomplished in a short and simple synthetic route. A selected set of 17 synthesized PSEs were evaluated for the antiproliferative activity against human cervical epithelioid carcinoma (HeLa) cell lines using MTS assay method. Eleven (11) compounds showed significant antiproliferative activity with their IC(50)values ranging from 0.16 to 6.01 μM. The structure-activity-relationship studies revealed that the antiproliferative activity is influenced by the lipophilicity and number of feruloyl substituents on these compounds. The preliminary screening indicated that these compounds are potentially very valuable source for new lead chemotherapeutics.

Understanding the Nano-topography Changes and Cellular Influences Resulting from the Surface Adsorption of Human Hair Keratins

Advanced Healthcare Materials. Jul, 2012  |  Pubmed ID: 23184785

Recent interest in the use of human hair keratins as a biomaterial has grown, fuelled by improvements in keratin extraction methods and better understanding of keratin bioactivity. The use of keratins as a bioactive coating for in vitro cell culture studies is an attractive proposition. In this light, the surface adsorption of human hair keratins onto tissue culture polystyrene surfaces has been investigated. Keratin density, nano-topography and hydrophobicity of keratin coated surfaces were characterized. To understand the cellular influence of these coated surfaces, murine L929 fibroblasts were cultured on them and evaluated for cytotoxicity, proliferation, metabolic activity and detachment behaviors compared to collagen type 1 coated surfaces. Keratins were deposited up to a density of 650 ng/cm(2) when a coating concentration of 80 μg/ml or higher was used. The surface features formed by adsorbed keratins also changed in a coating concentration dependent manner. These surfaces improved L929 mouse fibroblast adhesion and proliferation in comparison to uncoated and collagen type 1 coated tissue culture polystyrene. Furthermore, the expression of fibronectin was accelerated on surfaces coated with solutions of higher keratin concentrations. These results suggest that human hair keratins can be used as a viable surface coating material to enhance substrate compliance for culturing cells.

Formation of a Nano-pattering NiTi Surface with Ni-depleted Superficial Layer to Promote Corrosion Resistance and Endothelial Cell-material Interaction

Journal of Materials Science. Materials in Medicine. Jan, 2013  |  Pubmed ID: 23053806

Zirconium ion implantation was performed on NiTi alloy to suppress Ni ion release as well as to improve corrosion resistance and cell-material interaction. A thicker Ni-depleted nano-scale composite layer formed after Zr implantation and the corrosion resistance was evidently increased in aspects of increased E(br) - E(corr) (difference between corrosion potential and breakdown potential) and decreased corrosion current density. 2.5/2 NiTi sample possessed the highest E(br) - E(corr), more than 500 mV higher than that of untreated NiTi, suggesting a significant improvement on pitting corrosion resistance. Ni ion release rate of Zr-NiTi was decreased due to the depletion of Ni in the superficial surface layer and the diffusion resistance effect of the ZrO(2)/TiO(2) nano-film. Increased surface wettability induced by increased surface roughness was obtained after Zr implantation. Zr-NiTi samples were found to be favorable to endothelial cells (ECs) proliferation, especially after 5 and 7 days culture.

A Mathematical Model Predicting the Coculture Dynamics of Endothelial and Mesenchymal Stem Cells for Tissue Regeneration

Tissue Engineering. Part A. May, 2013  |  Pubmed ID: 23216214

In most tissue engineering applications, understanding the factors affecting the growth dynamics of coculture systems is crucial for directing the population toward a desirable regenerative process. Yet, no comprehensive analysis method exists to quantify coculture population dynamics, let alone, a unifying model addressing the "environmental" factors influencing cell growth, all together. Here we suggest a modification of the Lotka-Volterra model to analyze the population dynamics of cocultured cells and predict their growth profiles for tissue engineering applications. This model, commonly used to describe the population dynamics of a prey and predator sharing a closed ecological niche, was found to fit our empirical data on cocultures of endothelial cells (ECs) and mesenchymal stem cells (MSCs) that have been widely investigated for their regenerative potential. Applying this model to cocultures of this sort allows us to quantify the effect that culturing conditions have on the way cell growth is affected by the same cells or by the other cells in the coculture. We found that in most cases, EC growth was inhibited by the same cells but promoted by MSCs. The principles resulting from this analysis can be used in various applications to guide the population toward a desired direction while shedding new light on the fundamental interactions between ECs and MSCs. Similar results were also demonstrated on complex substrates made from decellularized porcine cardiac extracellular matrix, where growth occurred only after coculturing ECs and MSCs together. Finally, this unique implementation of the Lotka-Volterra model may also be regarded as a roadmap for using such models with other potentially regenerative cocultures in various applications.

Human Mesenchymal Stem-cell Behaviour on Direct Laser Micropatterned Electrospun Scaffolds with Hierarchical Structures

Macromolecular Bioscience. Mar, 2013  |  Pubmed ID: 23233197

Direct laser machining and electrospinning are utilized to obtain a bi-layered hybrid scaffold with hierarchical topographical features to mimic extracellular matrix-like microenvironment of cells. Adult bone marrow derived human mesenchymal stem cells (hMSCs) are cultured in vitro in these hybrid scaffolds, and cell orientation, proliferation, viability, and differentiation are evaluated. The results show that this novel hybrid scaffold not only supports cell growth like traditional scaffolds, but also elicits positive responses from the cells, like lineage commitment and alignment, which are essential features of future scaffolds.

A Mathematical Model for Analyzing the Elasticity, Viscosity, and Failure of Soft Tissue: Comparison of Native and Decellularized Porcine Cardiac Extracellular Matrix for Tissue Engineering

Tissue Engineering. Part C, Methods. Aug, 2013  |  Pubmed ID: 23265414

The clinical success of tissue-engineered constructs commonly requires mechanical properties that closely mimic those of the human tissue. Determining the viscoelastic properties of such biomaterials and the factors governing their failure profiles, however, has proven challenging, although collecting extensive data regarding their tensile behavior is straightforward. The easily calculated Young's modulus remains the most reported mechanical measure, regardless of its limitations, even though single-relaxation-time (SRT) models can provide much more information, which remain scarce due to a lack of manageable tools for implementing these models. We developed an easy-to-use algorithm for applying the Zener SRT model and determining the elastic moduli, viscosity, and failure profiles of materials under different mechanical tests in a user-independent manner. The algorithm was validated on the data resulting from tensile tests on native and decellularized porcine cardiac tissue, previously suggested as a promising scaffold material for cardiac tissue engineering. This analysis yields new and more accurate measurements such as the elastic moduli and viscosity, the model's relaxation time, and information on the factors governing the materials' failure profiles. These measurements indicate that the viscoelasticity and strength of the decellularized acellular extracellular matrix (ECM) are similar to those of native tissue, although its elasticity and apparent viscosity are higher. Nonetheless, reseeding and culturing the ECM with mesenchymal stem cells was shown to partially restore the mechanical properties lost after decellularization. We propose this algorithm as a platform for soft-tissue analysis that can provide comparable and unbiased measures for characterizing viscoelastic biomaterials commonly used in tissue engineering.

In-vivo Evaluation of an in Situ Polymer Precipitation Delivery System for a Novel Natriuretic Peptide

PloS One. 2013  |  Pubmed ID: 23441143

This study reports on the release of a novel natriuretic peptide, CD-NP, from an in situ polymer precipitation delivery system. Following extensive screening of in-vitro release profiles, an in-vivo evaluation of the efficacy of the delivery system was carried out in Wistar rats. Gel injection was performed subcutaneously on the back of the rats. A secondary messenger, cyclic Guanosine 3'5' Monophosphate (cGMP), was tested for verification of CD-NP bioactivity, in addition to direct measurements of CD-NP levels in plasma and urine using a radio-immuno assay. Plasma evaluation showed an elevated level of CD-NP over 3 weeks' duration. Unexpectedly, plasma cGMP level followed a decreasing trend over the same duration despite high CD-NP level. Loss of drug bioactivity was ruled out as a high level of CD-NP and cGMP excretion was observed in the treatment group as compared to baseline readings. This unexpected low-plasma cGMP levels and high-urinary cGMP excretion suggest that there might be other compensatory responses to regulation of the CDNP bioactivity as a result of the high drug dosing. The results stress the importance of assessing the overall bioactivity of released drug (in-vivo) concurrently in addition to measuring its concentrations, to determine the correct release profile.

Optimization of Subconjunctival Biodegradable Microfilms for Sustained Drug Delivery to the Anterior Segment in a Small Animal Model

Investigative Ophthalmology & Visual Science. Apr, 2013  |  Pubmed ID: 23518771

We evaluated a biodegradable, sustained-release, prednisolone acetate (PA)-loaded poly[d,l-lactide-co-ε-caprolactone] (PLC) drug delivery system on its biocompatibility, feasibility and release characteristics in vitro and in vivo.

Development of a Novel Biodegradable Drug-eluting Ventilation Tube for Chronic Otitis Media with Effusion

The Laryngoscope. Jul, 2013  |  Pubmed ID: 23666715

To develop a novel drug-eluting biodegradable ventilation tube (VT), to evaluate in vitro sustained release and antibacterial adherence of ofloxacin-loaded biodegradable VT on Pseudomonas aeruginosa, and to evaluate in vivo biodegradation of VT in guinea pig ears.

Collagen-cellulose Composite Thin Films That Mimic Soft-tissue and Allow Stem-cell Orientation

Journal of Materials Science. Materials in Medicine. May, 2013  |  Pubmed ID: 23670603

Mechanical properties of collagen films are less than ideal for biomaterial development towards musculoskeletal repair or cardiovascular applications. Herein, we present a collagen-cellulose composite film (CCCF) compared against swine small intestine submucosa in regards to mechanical properties, cell growth, and histological analysis. CCCF was additionally characterized by FE-SEM, NMR, mass spectrometry, and Raman Microscopy to elucidate its physical structure, collagen-cellulose composition, and structure activity relationships. Mechanical properties of the CCCF were tested in both wet and dry environments, with anisotropic stress-strain curves that mimicked soft-tissue. Mesenchymal stem cells, human umbilical vein endothelial cells, and human coronary artery smooth muscle cells were able to proliferate on the collagen films with specific cell orientation. Mesenchymal stem cells had a higher proliferation index and were able to infiltrate CCCF to a higher degree than small intestine submucosa. With the underlying biological properties, we present a collagen-cellulose composite film towards forthcoming biomaterial-related applications.

Layer-by-layer Polyelectrolyte-polyester Hybrid Microcapsules for Encapsulation and Delivery of Hydrophobic Drugs

Biomacromolecules. Jul, 2013  |  Pubmed ID: 23692337

A two-step process is developed to form layer-by-layer (LbL) polyelectrolyte microcapsules, which are able to encapsulate and deliver hydrophobic drugs. Spherical porous calcium carbonate (CaCO3) microparticles were used as templates and coated with a poly(lactic acid-co-glycolic acid) (PLGA) layer containing hydrophobic compounds via an in situ precipitation gelling process. PLGA layers that precipitated from N-methyl-2-pyrrolidone (NMP) had a lower loading and smoother surface than those precipitated from acetone. The difference may be due to different viscosities and solvent exchange dynamics. In the second step, the successful coating of multilayer polyelectrolytes poly(allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS) onto the PLGA coated CaCO3 microparticles was confirmed with AFM and ζ-potential studies. The release of a model hydrophobic drug, ibuprofen, from these hybrid microcapsules with different numbers of PAH/PSS layers was investigated. It was found that the release of ibuprofen decreases with increasing layer numbers demonstrating the possibility to control the release of ibuprofen with these novel hybrid microcapsules. Besides loading of hydrophobic drugs, the interior of these microcapsules can also be loaded with hydrophilic compounds and functional nanoparticles as demonstrated by loading with Fe3O4 nanoparticles, forming magnetically responsive dual drug releasing carriers.

Cenderitide-eluting Film for Potential Cardiac Patch Applications

PloS One. 2013  |  Pubmed ID: 23861890

Cenderitide, also known as CD-NP, is a designer peptide developed by combining native mammalian c-type natriuretic peptide (CNP) and the C-terminus isolated from the dendroapis natriuretic peptide (DNP) of the venom from the green mamba. In early studies, intravenous and subcutaneous infusion of cenderitide was reported to reduce left ventricular (LV) mass and ameliorate cardiac remodelling. In this work, biodegradable polymeric films encapsulating CD-NP were developed and were investigated for their in vitro release and degradation characteristics. Subsequently, the bioactivity of released peptide and its effects on human cardiac fibroblast (HCF) were explored. We achieved sustained release from three films with low, intermediate and high release profiles for 30 days. Moreover, the bioactivity of released peptide was verified from the elevated production of cyclic guanosine monophospate (cGMP). The CD-NP released from films was able to inhibit the proliferation of hypertrophic HCF as well as suppress DNA synthesis in HCF. Furthermore, the sustained delivery from films showed comparable or superior suppressive actions on hypertrophic HCF compared to daily infusion of CD-NP. The results suggest that these films could be used to inhibit fibrosis and reduce cardiac remodelling via local delivery as cardiac patches.

A Biodegradable, Sustained-released, Prednisolone Acetate Microfilm Drug Delivery System Effectively Prolongs Corneal Allograft Survival in the Rat Keratoplasty Model

PloS One. 2013  |  Pubmed ID: 23940573

Frequent and long-term use of topical corticosteroids after corneal transplantation is necessary to prevent graft rejection. However, it relies heavily on patient compliance, and sustained therapeutic drug levels are often not achieved with administration of topical eye drops. A biodegradable drug delivery system with a controlled and sustained drug release may circumvent these limitations. In this study, we investigated the efficacy of a prednisolone acetate (PA)-loaded poly (d,l-lactide-co-ε-caprolactone) (PLC) microfilm drug delivery system on promoting the survival of allogeneic grafts after penetrating keratoplasty (PK) using a rat model. The drug release profiles of the microfilms were characterized (group 1). Subsequently, forty-eight PK were performed in four experimental groups: syngeneic control grafts (group 2), allogeneic control grafts (group 3), allogeneic grafts with subconjunctivally-implanted PA microfilm (group 4), and allogeneic grafts with PA eye drops (group 5; n = 12 in each). PA-loaded microfilm achieved a sustained and steady release at a rate of 0.006-0.009 mg/day, with a consistent aqueous drug concentration of 207-209 ng/ml. The mean survival days was >28 days in group 2, 9.9±0.8 days in group 3, 26.8±2.7 days in group 4, and 26.4±3.4 days in group 5 (P = 0.023 and P = 0.027 compared with group 3). Statistically significant decrease in CD4+, CD163+, CD 25+, and CD54+ cell infiltration was observed in group 4 and group 5 compared with group 3 (P<0.001). There was no significant difference in the mean survival and immunohistochemical analysis between group 4 and group 5. These results showed that sustained PA-loaded microfilm effectively prolongs corneal allograft survival. It is as effective as conventional PA eye drops, providing a promising clinically applicable alternative for patients undergoing corneal transplantation.

A New Design and Application of Bioelastomers for Better Control of Intraocular Pressure in a Glaucoma Drainage Device

Advanced Healthcare Materials. Feb, 2014  |  Pubmed ID: 23836600

Glaucoma drainage device (GDD) implantation is an effective method of lowering the intraocular pressure (IOP). Commonly used GDDs can be classified into nonvalved and valved. Although a stable IOP is critical, currently available devices often cause extreme IOP fluctuations: nonvalved GDDs suffer from a risk of hypotony (IOP<5 mmHg), whereas valved GDDs have a higher risk ocular hypertensive (IOP>22 mmHg). It is hypothesized that a GDD with a valve designed to open around the time of onset of the hypertensive phase, would minimize IOP fluctuation. Accordingly, a valve fabricated from a biodegradable polymer poly(L-lactide-co-ϵ-caprolactone) (PLC 70/30) is evaluated in vitro and in vivo. The pressure response is compared with its non-degradable counterpart in in vitro studies of IOP. It is also established that in vitro, the biodegradability of the valve is programmed to occur over 12 weeks. In vivo, a steady and low IOP is achieved with the biodegradable valve and the hypertensive phase is significantly attenuated compared with the commercial device. Fibrotic encapsulation of the device is also minimized with the biodegradable valve in vivo.

Hyaluronic Acid-based Nanocomposite Hydrogels for Ocular Drug Delivery Applications

Journal of Biomedical Materials Research. Part A. Sep, 2014  |  Pubmed ID: 24124098

Hyaluronic acid (HA) is a widely investigated biomaterial for many therapeutic applications owing to its unique properties of biocompatibility, biodegradation, and viscoelasticity. HA being a natural component of eye tissue with significant role in wound healing is a natural choice as a carrier for ocular drug delivery, provided the incorporated drugs are released in a sustained manner. However, localized sustained release of drugs inside eye has been difficult to achieve because of the inability to retain carriers for long periods in the eye. Using noncrosslinked (soluble) HA offers limited control over site retention of drugs. In order to obtain prolonged sustained delivery, two HA-based composite hydrogels incorporating nanocarriers, have been synthesized and characterized for swelling, rheology, degradation, and in vitro release of latanoprost, a drug used to reduce intraocular pressure. The HA is first chemically modified, mixed with drug-loaded liposomes, and then crosslinked to obtain nanocomposite hydrogels. In vitro release study shows longer sustained release of latanoprost from composite hydrogels as compared to liposomes or hydrogels alone indicating additional resistance to drug diffusion because of the incorporation of liposomes inside the hydrogels. It is believed that these nanocomposite hydrogels, with controlled degradation properties and sustained release, could serve as potential drug delivery systems for many ocular diseases.

Influence of Soluble PEG-OH Incorporation in a 3D Cell-laden PEG-fibrinogen (PF) Hydrogel on Smooth Muscle Cell Morphology and Growth

Journal of Biomaterials Science. Polymer Edition. 2014  |  Pubmed ID: 24304216

We have been able to control hydrogel compliance and cell spreading in a three-dimensional (3D) cell-laden system (hydrogel) using soluble PEG-OH. This was accomplished by encapsulating smooth muscle cells (SMCs) into poly(ethylene glycol)-fibrinogen (PEG-fibrinogen or PF) with poly(ethylene glycol)-diol (PEG-OH) as a macromolecular leachant. The cell-encapsulating hydrogels were prepared with three concentrations of soluble PEG-OH having a mass of 10 kDa (1, 5 and 10% w/v). Rheology was used to measure the elastic (storage) component of the complex shear modulus of these hydrogels, while quantitative morphometrics were used to characterize SMC morphology. PF hydrogel with a higher amount of PEG-OH displayed a lower storage modulus and a higher elongated cell morphology of SMCs. Structural changes of PF hydrogels mainly owing to gelation-induced phase separation imparted by the soluble PEG-OH in 3D cell-laden hydrogels dramatically affected both the properties of the hydrogel network including the modulus as well as cell spreading.

Biomaterials and Design in Occlusion Devices for Cardiac Defects: a Review

Acta Biomaterialia. Mar, 2014  |  Pubmed ID: 24334144

This review examines the biomaterials used in occlusion devices for cardiac defects, and how the choice of these materials is dictated by design. Specifically, the devices used in three major applications, the atrial septal defect, the ventricular septal defect and the patent ductus arteriosus, are examined critically. A number of different devices are available, with varied performance in deployment and sealing. There is no device in any of the three categories that satisfies fully the range of requirements, and all have associated complications. The type and rate of complications are different among different devices. The short-term (immediate) complications are addressed by immediate retrieval. For longer-term complications, most of which can be fatal, currently only surgical retrieval and replacement are possible. Most of these longer-term complications can be alleviated by the use of fully degradable devices, which will eliminate concerns regarding the use of metals inside the heart, and if fully endothelialized, also minimize migration concerns. On the other hand, the lower moduli of currently available biodegradable materials need to be augmented. Improvements in the stiffness required for deployment can be accomplished with the use of fillers, nano- or micro-sized, and an example of this are radiopaque fillers.

Solid/Hollow Depots for Drug Delivery, Part 1: Effect of Drug Characteristics and Polymer Molecular Weight on the Phase-inversion Dynamics, Depot Morphology, and Drug Release

Journal of Pharmaceutical Sciences. Feb, 2014  |  Pubmed ID: 24357252

The objective of this research was to evaluate the effect of drug characteristics and polymer molecular weight (MW) on phase-inversion dynamics, depot morphology, and drug release in injectable in situ depot-forming drug delivery systems. Two poly(lactide-co-glycolide) (50:50) polymers with different MW (RG502 and RG504) and two drugs with different hydrophilicity (metoclopramide salt and metoclopramide base) were studied here. The drug release from injectable depots, the polymer MW changes, and the cross-sectional depot morphologies were investigated, respectively. The results show that the initial drug release from high-MW polymer RG504 was always faster than that from low-MW polymer RG502, regardless of the drug type. Interestingly, depot morphology shows the development of a hollow core for RG502, whereas RG504 forms a solid core. The relationship of the depot morphology to release kinetics is proposed based on these observations. The use of basic drug catalyzes polymer degradation, during processing and over time. These affect starting MW and subsequent MW, and the effect on release kinetics is consistent with the general effects of MW. This research suggests that the polymer MW is an important effect on the polymer phase inversion kinetics, and thus the resultant depot morphology.

Sustained Drug Release in Nanomedicine: a Long-acting Nanocarrier-based Formulation for Glaucoma

ACS Nano. Jan, 2014  |  Pubmed ID: 24392729

Therapeutic nanomedicine has concentrated mostly on anticancer therapy by making use of the nanosize for targeted therapy. Such nanocarriers are not expected to have sustained release of the bioactive molecule beyond a few days. There are other conditions where patients can benefit from sustained duration of action following a single instillation, but achieving this has been difficult in nanosized carriers. An important prerequisite for sustained delivery over several months is to have sufficiently high drug loading, without disruption or changes to the shape of the nanocarriers. Here we report on successful development of a drug-encapsulated nanocarrier for reducing intraocular pressure in a diseased nonhuman primate model and explain why it has been possible to achieve sustained action in vivo. The drug is a prostaglandin derivative, latanoprost, while the carrier is a nanosized unilamellar vesicle. The mechanistic details of this unique drug-nanocarrier combination were elucidated by isothermal titration calorimetry. We show, using Cryo-TEM and dynamic light scattering, that the spherical shape of the liposomes is conserved even at the highest loading of latanoprost and that specific molecular interactions between the drug and the lipid are the reasons behind improved stability and sustained release. The in vivo results clearly attest to sustained efficacy of lowering the intraocular pressure for 120 days, making this an excellent candidate to be the first truly sustained-release nanomedicine product. The mechanistic details we have uncovered should enable development of similar systems for other conditions where sustained release from nanocarriers is desired.

Induction of Myogenic Differentiation of Human Mesenchymal Stem Cells Cultured on Notch Agonist (Jagged-1) Modified Biodegradable Scaffold Surface

ACS Applied Materials & Interfaces. Feb, 2014  |  Pubmed ID: 24405311

Engineered scaffold surface provides stem cells with vital cues that could determine the eventual fate of stem cells. In this work, biodegradable poly(L-lactide-co-ε-caprolactone) (PLCL) scaffold conjugated with Notch agonist-Jagged-1(JAG) peptide (2.1 kDa) was prepared to initiate myogenic differentiation of human mesenchymal stem cells (hMSCs). The scaffold surface was activated with oxygen plasma and acrylic acid was engrafted via UV polymerization to form a surface bearing carboxylic groups. JAG peptide was subsequently immobilized onto the carboxylated scaffold surface. Surface chemistry and topography were examined using attenuated total reflection Fourier transform infrared, X-ray photoelectron spectroscopy, and atomic force microscopy. Quantitative real time polymerase chain reaction analysis revealed activation of the Notch pathway; furthermore, several specific markers associated with myogenic but not osteogenic differentiation were shown to be up-regulated in hMSCs cultured on the engineered surface. The pro-myocardial effect of surface bound JAG peptide was further affirmed via immunodetection of the distinct myocardial marker, cardiac troponin T. Collectively, our results suggest that PLCL conjugated JAG peptide is a viable strategy to enhance the functional potential of scaffolds to be used as a bioengineered cardiac patch in myocardial infarction repair.

Layer-by-layer Nanoparticles As an Efficient SiRNA Delivery Vehicle for SPARC Silencing

Small (Weinheim an Der Bergstrasse, Germany). May, 2014  |  Pubmed ID: 24510544

Efficient and safe delivery systems for siRNA therapeutics remain a challenge. Elevated secreted protein, acidic, and rich in cysteine (SPARC) protein expression is associated with tissue scarring and fibrosis. Here we investigate the feasibility of encapsulating SPARC-siRNA in the bilayers of layer-by-layer (LbL) nanoparticles (NPs) with poly(L-arginine) (ARG) and dextran (DXS) as polyelectrolytes. Cellular binding and uptake of LbL NPs as well as siRNA delivery were studied in FibroGRO cells. siGLO-siRNA and SPARC-siRNA were efficiently coated onto hydroxyapatite nanoparticles. The multilayered NPs were characterized with regard to particle size, zeta potential and surface morphology using dynamic light scattering and transmission electron microscopy. The SPARC-gene silencing and mRNA levels were analyzed using ChemiDOC western blot technique and RT-PCR. The multilayer SPARC-siRNA incorporated nanoparticles are about 200 nm in diameter and are efficiently internalized into FibroGRO cells. Their intracellular fate was also followed by tagging with suitable reporter siRNA as well as with lysotracker dye; confocal microscopy clearly indicates endosomal escape of the particles. Significant (60%) SPARC-gene knock down was achieved by using 0.4 pmole siRNA/μg of LbL NPs in FibroGRO cells and the relative expression of SPARC mRNA reduced significantly (60%) against untreated cells. The cytotoxicity as evaluated by xCelligence real-time cell proliferation and MTT cell assay, indicated that the SPARC-siRNA-loaded LbL NPs are non-toxic. In conclusion, the LbL NP system described provides a promising, safe and efficient delivery platform as a non-viral vector for siRNA delivery that uses biopolymers to enhance the gene knock down efficiency for the development of siRNA therapeutics.

Characterization of a Bioactive Fiber Scaffold with Entrapped HUVECs in Coaxial Electrospun Core-shell Fiber

Biomatter. 2014  |  Pubmed ID: 24553126

Human umbilical vein endothelial cells (HUVECs) were successfully entrapped in polyethylene oxide (PEO) core /polycaprolactone (PCL) shell electrospun fibers thus creating a "bioactive fiber." The viability and release of biomolecules from the entrapped cells in the bioactive fibers were characterized. A key modification to the core solution was the inclusion of 50% fetal bovine serum (FBS), which improved cell viability substantially. The fluorescein diacetate (FDA) staining revealed that the entrapped cells were intact and viable immediately after the electrospinning process. A long-term cell viability assay using AlamarBlue® showed that cells were viable for over two weeks. Secreted Interleukin-8 (IL-8) was monitored as a candidate released protein, which can also act as an indicator of HUVEC stress. These results demonstrated that HUVECs could be entrapped within the electrospun scaffold with the potential of controllable cell deposition and the creation of a bioactive fibrous scaffold with extended functionality.

Investigation of Cenderitide Controlled Release Platforms for Potential Local Treatment of Cardiovascular Pathology

Journal of Pharmaceutical Sciences. May, 2014  |  Pubmed ID: 24590596

In this work, we focused on the development and investigation of controlled release matrices for a novel cardiotherapeutic peptide, cenderitide (CD-NP) that has shown to be useful for control of ventricular remodeling. To circumvent the hydrophilicity disparity between CD-NP and hydrophobic polymer matrix, a cosolvent system (water/dichloromethane) was selected for investigation. The effect of emulsification conditions, addition of poly(ethylene glycol) (PEG) and its copolymer on the release mechanism and profile were investigated. To verify the retention of bioactivity of entrapped CD-NP in different formulations, the generation of 3',5' cyclic guanosine monophospate (cGMP) and the inhibition of human cardiac fibroblast (HCF) were evaluated. The results showed that neat poly(ε-caprolactone) matrices carried out via two distinct emulsification conditions had either an unacceptably high burst or incomplete release of CD-NP; and the addition of PEG and its copolymer obtained intermediate profiles. Our confocal laser scanning microscopy and surface morphological investigations showed that the copolymer excipient was superior in playing stabilizer role by colocalizing and redistributing peptide throughout the matrix, making the release less sensitive to emulsification conditions. Furthermore, the released CD-NP is able to generate the cGMP and inhibit the HCF proliferation. Our investigations showed that CD-NP-loaded platforms can be a feasible option to provide sustained antifibrotic moderation of fibrotic scar formation and be potentially used to alleviate the adverse effects of cardiac remodeling.

Release Retardation of Model Protein on Polyelectrolyte-coated PLGA Nano- and Microparticles

PloS One. 2014  |  Pubmed ID: 24647768

PEM capsules have been proposed for vehicles of drug microencapsulation, with the release triggered by pH, salt, magnetic field, or light. When built on another carrier encapsulating drugs, such as nanoparticles, it could provide additional release barrier to the releasing drug, providing further control to drug release. Although liposomes have received considerable attention with PEM coating for sustained drug release, similar results employing PEM built on poly(lactic-co-lycolic acid) (PLGA) particles is scant. In this work, we demonstrate that the build-up pH and polyelectrolyte pairs of PEM affect the release retardation of BSA from PLGA particles. PAH/PSS pair, the most commonly used polyelectrolyte pair, was used in comparison with PLL/DES. In addition, we also demonstrate that the release retardation effect of PEM-coated PLGA particles diminishes as the particle size increases. We attribute this to the diminishing relative thickness of the PEM coating with respect to the size of the particle as the particle size increases, reducing the diffusional resistance of the PEM.

Tuning Model Drug Release and Soft-tissue Bioadhesion of Polyester Films by Plasma Post-treatment

ACS Applied Materials & Interfaces. Apr, 2014  |  Pubmed ID: 24666261

Plasma treatments are investigated as a post-production method of tuning drug release and bioadhesion of poly(lactic-co-glycolic acid) (PLGA) thin films. PLGA films were treated under varying conditions by controlling gas flow rate, composition, treatment time, and radio frequency (RF) power. In vitro release of the drug-like molecule fluorescein diacetate (FDAc) from plasma-treated PLGA was tunable by controlling RF power; an increase of 65% cumulative release is reported compared to controls. Bioadhesion was sensitive to RF power and treatment time, assessed using ex vivo shear-stress tests with wetted swine aorta. We report a maximum bioadhesion ∼6-fold that of controls and 5-fold that of DOPA-based mussel adhesives tested to swine skin.1 The novelty of this post-treatment is the activation of a hydrophobic polyester film for bioadhesion, which can be quenched, while simultaneously tuning drug-release kinetics. This exemplifies the promise of plasma post-treatment for in-clinic bioadhesive activation, along with technological advancements, i.e., atmospheric plasma and hand-held "plasma pencils".

Evaluation of a Prednisolone Acetate-loaded Subconjunctival Implant for the Treatment of Recurrent Uveitis in a Rabbit Model

PloS One. 2014  |  Pubmed ID: 24842851

To assess the efficacy of a biodegradable, prednisolone acetate implant in a rabbit uveitis model.

The Mechanical Behavior and Biocompatibility of Polymer Blends for Patent Ductus Arteriosus (PDA) Occlusion Device

Journal of the Mechanical Behavior of Biomedical Materials. Aug, 2014  |  Pubmed ID: 24846584

Patent Ductus Arteriosus (PDA) is a cardiovascular defect that occurs in 1 out of every 2000 births, and if left untreated, may lead to severe cardiovascular problems. Current options for occluding utilize meta scaffolds with polymer fabric, and are permanent. The purpose of this study was to develop a fully degradable occluder for the closure of PDA, that can be deployed percutaneously without open-heart surgery. For percutaneous deployment, both elasticity and sufficient mechanical strength are required of the device components. As this combination of properties is not achievable with currently-available homo- or copolymers, blends of biodegradable poly(ε-caprolactone) (PCL) and poly(L-lactide-co-ε-caprolactone) (PLC) with various compositions were studied as the potential material for the PDA occlusion device. Microstructures of this blend were characterized by differential scanning calorimetry (DSC) and tensile tests. DSC results demonstrated the immiscibility between PCL and its copolymer PLC. Furthermore, the mechanical properties, i.e. elastic modulus and strain recovery, of the blends could be largely tailored by changing the continuous phase component. Based on the thermo-mechanical tests, suitable blends were selected to fabricate a prototype of PDA occluder and its in vitro performance, in term of device recovery (from its sheathed configuration), biodegradation rate and blood compatibility, was evaluated. The current results indicate that the device is able to recover elastically from a sheath within 2-3min for deployment; the device starts to disintegrate within 5-6 months, and the materials have no adverse effects on the platelet and leucocyte components of the blood. Biocompatibility implantation studies of the device showed acceptable tissue response. Finally, an artificial PDA conduit was created in a pig model, and the device deployment was tested from a sheath: the device recovered within 2-3min of unsheathing and fully sealed the conduit, the device remains stable and is completely covered by tissue at 1 month follow up. Thus, a novel prototype for PDA occlusion that is fully degradable has been developed to overcome the limitations of the currently used metal/fabric devices.

In Vitro Evaluation of Cenderitide-eluting Stent I -an Antirestenosis and Proendothelization Approach

Journal of Pharmaceutical Sciences. Nov, 2014  |  Pubmed ID: 25223419

Despite the success that drug-eluting stents (DESs) have achieved for minimizing in-stent restenosis (ISR), the antirestenotic agents used in DES have been implicated in delayed endothelial healing and impairment of endothelial functions. Cenderitide (CD-NP) is a novel antiproliferation chimeric peptide of semiendothelial origin; thus, this paper aims to demonstrate the selectivity aspect of this new peptide via in vitro evaluation on key players in ISR-smooth muscle cells (SMCs) and endothelial cells. The microbicinchoninic acid protein assay was used to investigate the CD-NP release from films and stents. Cenderitide-containing films blended with poly(ethylene glycol) and its copolymer exhibited higher release kinetics compared with neat poly(ε-caprolactone) (PCL) formulation. Cenderitide-eluting stents (CES) was produced by coating bare metallic stents with CD-NP entrapped PCL using an ultrasonic spray coater. The investigation of CD-NP on in vitro cells revealed that CD-NP inhibits human coronary smooth muscle cells (HCaSMCs) proliferation but exhibits no effects on human umbilical vein endothelial cells (HUVECs) proliferation. Moreover, CD-NP released up to 7 days displayed inhibitory effects on SMCs proliferation. The CES produced in this work shows that the released CD-NP inhibits HCaSMCs proliferation but did not hamper HUVECs proliferation in vitro, suggesting that it has potential to reduce ISR without retarding the endothelialization healing in vivo.

Nanomedicine for Glaucoma: Sustained Release Latanoprost Offers a New Therapeutic Option with Substantial Benefits over Eyedrops

Drug Delivery and Translational Research. Aug, 2014  |  Pubmed ID: 25787063

Glaucoma is a chronic progressive optic neuropathy that is characterized by optic nerve changes and visual field loss. Elevated intraocular pressure (IOP) is the main modifiable risk factor. Chronic instillation of daily eyedrops to lower IOP is the primary treatment of choice, although it requires patient adherence and correct performance. We have developed a nanoliposome drug delivery system for the longer term delivery of latanoprost. In the present open-label, pilot study, the safety and efficacy of a single subconjunctival injection of liposomal latanoprost was evaluated in six subjects with a diagnosis of either ocular hypertension (OHT) or primary open-angle glaucoma (POAG). Subconjunctival injection of liposomal latanoprost was well tolerated by all six subjects. From a baseline IOP of 27.55 ± 3.25 mmHg, the mean IOP decreased within 1 h to 14.52 ± 3.31 mmHg (range 10-18 mmHg). This represented a mean decrease of 13.03 ± 2.88 mmHg (range 9-17 mmHg), or 47.43 ± 10.05 % (range 37-63 %). A clinically and statistically significant IOP reduction (≥20 % IOP reduction, P = 0.001 to 0.049) was observed through 3 months after injection. The nanomedicine reported here is the first nanocarrier formulation that has an extended duration of action in humans, beyond a couple of weeks. The findings in this study open up a new treatment modality, which will greatly enhance patient compliance and improve treatment outcomes. The current study provides the evidence and support for further clinical studies of liposomal latanoprost in the treatment of glaucoma.

Pushing the Envelope in Tissue Engineering: Ex Vivo Production of Thick Vascularized Cardiac Extracellular Matrix Constructs

Tissue Engineering. Part A. May, 2015  |  Pubmed ID: 25602926

Functional vascularization is a prerequisite for cardiac tissue engineering of constructs with physiological thicknesses. We previously reported the successful preservation of main vascular conduits in isolated thick acellular porcine cardiac ventricular ECM (pcECM). We now unveil this scaffold's potential in supporting human cardiomyocytes and promoting new blood vessel development ex vivo, providing long-term cell support in the construct bulk. A custom-designed perfusion bioreactor was developed to remodel such vascularization ex vivo, demonstrating, for the first time, functional angiogenesis in vitro with various stages of vessel maturation supporting up to 1.7 mm thick constructs. A robust methodology was developed to assess the pcECM maximal cell capacity, which resembled the human heart cell density. Taken together these results demonstrate feasibility of producing physiological-like constructs such as the thick pcECM suggested here as a prospective treatment for end-stage heart failure. Methodologies reported herein may also benefit other tissues, offering a valuable in vitro setting for "thick-tissue" engineering strategies toward large animal in vivo studies.

A Fully Biodegradable Patent Ductus Arteriosus Occlude

Journal of Materials Science. Materials in Medicine. Feb, 2015  |  Pubmed ID: 25649512

The purpose of this study was to develop a fully degradable occluder for the closure of PDA, which can be deployed percutaneously. The blends of biodegradable poly(ε-caprolactone) and poly(L-lactide-co-ε-caprolactone) with various compositions were studied as the potential material. The mechanical properties, i.e. elastic modulus and strain recovery, of the blends could be largely tailored by changing the continuous phase component. Moreover, the suitable blends were selected to fabricate a prototype and its in vitro biodegradation rate and blood compatibility, was evaluated. The current results indicate that no adverse effect on the platelet and leukocyte components of the blood. Biocompatibility implantation studies of the device showed acceptable tissue response. Finally, an artificial PDA conduit was created in a pig, and the device deployment was tested from a sheath: the device recovered within 2-3 min of unsheathing and fully sealed the conduit.

Quantification of Aldehyde Terminated Heparin by SEC-MALLS-UV for the Surface Functionalization of Polycaprolactone Biomaterials

Colloids and Surfaces. B, Biointerfaces. Aug, 2015  |  Pubmed ID: 26052108

A straight forward strategy of heparin surface grafting employs a terminal reactive-aldehyde group introduced through nitrous acid depolymerization. An advanced method that allows simultaneously monitoring of both heparin molar mass and monomer/aldehyde ratio by size exclusion chromatography, multi-angle laser light scattering and UV-absorbance (SEC-MALLS-UV) has been developed to improve upon heparin surface grafting. Advancements over older methods allow quantitative characterization by direct (aldehyde absorbance) and indirect (Schiff-based absorbance) evaluation of terminal functional aldehydes. The indirect quantitation of functional aldehydes through labeling with aniline (and the formation of a Schiff-base) allows independent quantitation of both polymer mass and terminal functional groups with the applicable UV mass extinction coefficients determined. The protocol was subsequently used to synthesize an optimized heparin-aldehyde that had minimal polydispersity (PDI<2) and high reaction yields (yield >60% by mass). The 8 kDa weight averaged molar mass heparin-aldehyde was then grafted on polycaprolactone (PCL), a common implant material. This optimized heparin-aldehyde retained its antithrombin activity, assessed in freshly drawn blood or surface immobilized on PCL films. Anticoagulant activity was equal to or better than the 24 kDa unmodified heparin it was fragmented from.

A Biodegradable Ocular Implant for Long-term Suppression of Intraocular Pressure

Drug Delivery and Translational Research. Oct, 2015  |  Pubmed ID: 26100093

Timolol maleate (TM) has been used for many years for the reduction of intraocular pressure (IOP) in glaucoma patients. However, the topical mode of administration (eyedrops) is far from optimal because of the issues of low bioavailability, high drug wastage, and lack of patient compliance. Suboptimal control of the IOP leads to disease progression and eventually to blindness. Ideally, TM is delivered to the patient so that its action is both localized and sustained for 3 months or more. In this work, we developed a subconjunctival TM microfilm for sustained, long-term delivery of TM to the eyes, using the biodegradable elastomer poly(lactide-co-caprolactone) (PLC). The copolymer is biocompatible and has flexibility and mechanical characteristics suitable for a patient-acceptable implant. Controlling the release of TM for 3 months is challenging, and this work describes how, by using a combination of multilayering and blending with poly(ethylene glycol) (PEG) copolymers, we were able to develop a TM-incorporated biodegradable film that can deliver TM at a therapeutic dose for 90 days in vitro. The data was further confirmed in a diseased primate model, with sustained IOP-lowering effects for 5 months with a single implant, with acceptable biocompatibility and partial degradation.

Accelerating the Translation of Nanomaterials in Biomedicine

ACS Nano. Jul, 2015  |  Pubmed ID: 26115196

Due to their size and tailorable physicochemical properties, nanomaterials are an emerging class of structures utilized in biomedical applications. There are now many prominent examples of nanomaterials being used to improve human health, in areas ranging from imaging and diagnostics to therapeutics and regenerative medicine. An overview of these examples reveals several common areas of synergy and future challenges. This Nano Focus discusses the current status and future potential of promising nanomaterials and their translation from the laboratory to the clinic, by highlighting a handful of successful examples.

3D Patterned Substrates for Bioartificial Blood Vessels - The Effect of Hydrogels on Aligned Cells on a Biomaterial Surface

Acta Biomaterialia. Oct, 2015  |  Pubmed ID: 26297885

The optimal bio-artificial blood vessel construct is one that has a compliant tubular core with circumferentially aligned smooth muscle cells (SMCs). Obtaining this well-aligned pattern of SMCs on a scaffold is highly beneficial as this cellular orientation preserves the SMC contractile phenotype. We used 3D patterning to create channels on a polycaprolactone (PCL) scaffold; SMCs were then found to be aligned within the microchannels. To preserve this alignment, and to provide a protective coating that could further incorporate cells, we evaluated the use of two hydrogels, one based on poly(ethylene glycol) diacrylate (PEGDA) and the other based on gelatin. Hydrogels were either physically coated on the PCL surfaces or covalently linked via suitable surface modification of PCL. For covalent immobilization of PEGDA hydrogel, alkene groups were introduced on PCL, while for gelatin covalent linkage, serum proteins were introduced. It is, however, crucial that the hydrogel coating does not disrupt the cellular patterning and distribution. We show in this work that both the process of coating as well as the nature of the coating are critical to preservation of the aligned SMCs. The covalent coating methods involving the crosslinking of hydrogels with the surface of PCL films promoted hydrogel retention time on the film as compared with physical deposition. Furthermore, subsequent hydrogel degradation is affected by the components of the cell culture medium, hinting at a possible route to in vivo biodegradation.

Surface Modification of PMMA to Improve Adhesion to Corneal Substitutes in a Synthetic Core-Skirt Keratoprosthesis

ACS Applied Materials & Interfaces. Oct, 2015  |  Pubmed ID: 26389670

Patients with advanced corneal disease do poorly with conventional corneal transplantation and require a keratoprosthesis (KPro) for visual rehabilitation. The most widely used KPro is constructed using poly(methyl methacrylate) (PMMA) in the central optical core and a donor cornea as skirt material. In many cases, poor adherence between the PMMA and the soft corneal tissue is responsible for device "extrusion" and bacterial infiltration. The interfacial adhesion between the tissue and the PMMA was therefore critical to successful implantation and device longevity. In our approach, we modified the PMMA surface using oxygen plasma (plasma group); plasma followed by calcium phosphate (CaP) coating (p-CaP); dopamine followed by CaP coating (d-CaP); or plasma followed by coating with (3-aminopropyl)triethoxysilane (3-APTES). To create a synthetic KPro model, we constructed and attached 500 μm thick collagen type I hydrogel on the modified PMMA surfaces. Surface modifications produced significantly improved interfacial adhesion strength compared to untreated PMMA (p < 0.001). The p-CaP group yielded the best interfacial adhesion with the hydrogel (177 ± 27 mN/cm(2)) followed by d-CaP (168 ± 31 mN/cm(2)), 3-APTES (145 ± 12 mN/cm(2)), and plasma (119 ± 10 mN/cm(2)). Longer-term stability of the adhesion was achieved by d-CaP, which, after 14 and 28 days of incubation in phosphate buffered saline, yielded 164 ± 25 mN/cm(2) (p = 0.906 compared to adhesion at day 1) and 131 ± 20 mN/cm(2) (p = 0.053), respectively. In contrast, significant reduction of adhesion strength was observed in p-CaP group over time (p < 0.001). All surface coatings were biocompatible to human corneal stromal fibroblasts, except for the 3-APTES group, which showed no live cells at 72 h of culture. In contrast, cells on d-CaP surface showed good anchorage, evidenced by the expression of focal adhesion complex (paxillin and vinculin), and prominent filopodia protrusions. In conclusion, d-CaP can not only enhance and provide stability to the adhesion of collagen hydrogel on the PMMA surface but also promote biointegration.

Smooth Muscle Cell Alignment and Phenotype Control by Melt Spun Polycaprolactone Fibers for Seeding of Tissue Engineered Blood Vessels

International Journal of Biomaterials. 2015  |  Pubmed ID: 26413093

A method has been developed to induce and retain a contractile phenotype for vascular smooth muscle cells, as the first step towards the development of a biomimetic blood vessel construct with minimal compliance mismatch. Melt spun PCL fibers were deposited on a mandrel to form aligned fibers of 10 μm in diameter. The fibers were bonded into aligned arrangement through dip coating in chitosan solution. This formed a surface of parallel grooves, 10 μm deep by 10 μm across, presenting a surface layer of chitosan to promote cell surface interactions. The aligned fiber surface was used to culture cells present in the vascular wall, in particular fibroblasts and smooth muscle cells. This topography induced "surface guidance" over the orientation of the cells, which adopted an elongated spindle-like morphology, whereas cells on the unpatterned control surface did not show such orientation, assuming more rhomboid shapes. The preservation of VSMC contractile phenotype on the aligned scaffold was demonstrated by the retention of α-SMA expression after several days of culture. The effect was assessed on a prototype vascular graft prosthesis fabricated from polylactide caprolactone; VSMCs aligned longitudinally along a fiberless tube, whereas, for the aligned fiber coated tubes, the VSMCs aligned in the required circumferential orientation.

Bioabsorbable Vascular Scaffold Overexpansion: Insights from in Vitro Post-expansion Experiments

EuroIntervention : Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. Mar, 2016  |  Pubmed ID: 26151954

While bioresorbable vascular scaffolds (BVS) are increasingly used in clinical practice, their behaviour when post-dilated beyond their recommended maximum overexpansion diameter remains sparsely documented. We aimed to test the overexpansion of the BVS scaffold in vitro and evaluate the impact of excessive scaffold oversizing on focal point support.

In Vivo Evaluation of Cenderitide-Eluting Stent (CES) II

Annals of Biomedical Engineering. Feb, 2016  |  Pubmed ID: 26178873

The use of drug-eluting coronary stents has led to significant reduction in in-stent restenosis (ISR), but led to delayed endothelialization, necessitating the prolonged use of expensive anti-thrombotic drugs with their side-effects. Cenderitide (CD-NP) is a novel anti-proliferative chimeric peptide of semi-endothelial origin. Our previous work in vitro has demonstrated; that the smooth muscle cells were inhibited significantly more than endothelial cells which is the desirable feature of an anti-restenosis drug. This work reports the effects of implantation of a centeritide-eluting stent (CES) on ISR and endothelialization in an in vivo model. CESs were produced by coating bare metallic stents with CD-NP entrapped in biodegradable poly(ε-caprolactone) using an ultrasonic spray coater. A total of 32 stents were successfully implanted into 16 pigs, and all animal survived for 28 days. The plasma levels of CD-NP were significantly higher in the CES group than in the control group (bare metal stents and polymer-coated stent) at post-stenting, indicating the successful release of CD-NP from the stent in vivo. Furthermore, SEM analysis results showed the greater endothelial coverage of the stent struts, as well as between the struts in CES group. Moreover, histological results showed mild inflammation, and low fibrin score at 28 days. However, plasma cGMP (second messenger, cyclic 3',5' guanosine monophosphate) does not show a significant difference, and the CES is also unable to show significant difference in terms on neointimal area and stenosis, in comparison to BMS at 28 days.

Nanofibril Scaffold Assisted MEMS Artificial Hydrogel Neuromasts for Enhanced Sensitivity Flow Sensing

Scientific Reports. Jan, 2016  |  Pubmed ID: 26763299

We present the development and testing of superficial neuromast-inspired flow sensors that also attain high sensitivity and resolution through a biomimetic hyaulronic acid-based hydrogel cupula dressing. The inspiration comes from the spatially distributed neuromasts of the blind cavefish that live in completely dark undersea caves; the sensors enable the fish to form three-dimensional flow and object maps, enabling them to maneuver efficiently in cluttered environments. A canopy shaped electrospun nanofibril scaffold, inspired by the cupular fibrils, assists the drop-casting process allowing the formation of a prolate spheroid-shaped artificial cupula. Rheological and nanoindentation characterizations showed that the Young's modulus of the artificial cupula closely matches the biological cupula (10-100 Pa). A comparative experimental study conducted to evaluate the sensitivities of the naked hair cell sensor and the cupula-dressed sensor in sensing steady-state flows demonstrated a sensitivity enhancement by 3.5-5 times due to the presence of hydrogel cupula. The novel strategies of sensor development presented in this report are applicable to the design and fabrication of other biomimetic sensors as well. The developed sensors can be used in the navigation and maneuvering of underwater robots, but can also find applications in biomedical and microfluidic devices.

Synthesis of Stiffness-tunable and Cell-responsive Gelatin-poly(ethylene Glycol) Hydrogel for Three-dimensional Cell Encapsulation

Journal of Biomedical Materials Research. Part A. Oct, 2016  |  Pubmed ID: 27170015

Biosynthetic poly(ethylene glycol) (PEG)-based hydrogels have been extensively investigated as extracellular matrix (ECM) mimicking gels as they retain the benefits of both ECM (biological cues) and synthetic hydrogels (tunable mechanical properties). In this article, we developed and characterized a new gelatin-PEG (GP) hydrogel that retains the benefits of gelatin and synthetic hydrogels. In this strategy, the thiolation of gelatin was accomplished by reacting with Traut's reagent; the thiolated gelatin was then conjugated to one end of PEG diacrylate (PEGDA) by Michael-type addition reaction. Two kinds of GP precursors, GP30 and GP60, were synthesized by changing the amount of Traut's reagent, while the weight ratio between thiolated-gelatin and PEGDA of GP30 and GP60 was 1.451:1 and 0.785:1, respectively. Finally, neonatal human dermal fibroblasts were encapsulated into the hydrogel by cross-linking the remaining double bonds of precursor under ultraviolet light. These GP hydrogels can encapsulate the fibroblasts in situ with high cell viability. Moreover, the behaviors of cells within the GP hydrogels can be modulated by varying the cross-linking density of GP hydrogel (storage modulus from 40 to 2000 Pa). In particular, this article showed that a minimum amount of cell-binding motifs (gelatin >2.30 wt/vol % and 44.0% dry weight percentage) are required for attachment; and appropriate initial rheological and structural properties (storage modulus <∼100 Pa and mesh size >∼150 nm) can accelerate the attachment of cells and improve cell viability. Hence, this mixed-hydrogel platform allows an easily control hydrogel structure and modulates cell behavior to reconstruct new tissue in the three-dimensional microenvironments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2401-2411, 2016.

Bioabsorbable Radiopaque Water-responsive Shape Memory Embolization Plug for Temporary Vascular Occlusion

Biomaterials. Sep, 2016  |  Pubmed ID: 27322962

We describe the preparation, characterization and evaluation of a biodegradable radiopaque water-triggered shape memory embolization plug for temporary vascular occlusion. The shape memory occluding device consists of a composite of a radio-opaque filler and a poly (dl-lactide-co-glycolide) (PLGA) blend, which was coated with a crosslinked poly (ethylene glycol) diacrylate (PEGDA) hydrogel. The mechanical properties, the degradation timeframe, the effect of programming conditions on the shape memory behaviour and the extent of radio-opacity for imaging were evaluated. Based on the tests, the mechanism responsible for the water-induced shape memory effect in such an embolization plug was elucidated. Suitable materials were optimized to fabricate an embolic plug prototype and its in vitro performance was evaluated as an occlusion rate (using a custom-built set up) and its biocompatibility. Finally, a feasibility study was conducted in vivo in a rabbit model to investigate the ease of device deployment, device migration and extent of vessel occlusion. The in vivo results demonstrated that the prototypes were visible under fluoroscopy and complete vascular occlusion occurred within 2 min of deployment of the prototypes in vivo. In conclusion, the developed embolization plug enables controlled and temporary vascular embolization, and is ready for safety studies.

Photosensitizer Anchored Gold Nanorods for Targeted Combinational Photothermal and Photodynamic Therapy

Chemical Communications (Cambridge, England). Jul, 2016  |  Pubmed ID: 27346609

Silylated zinc phthalocyanine (ZnPc) was anchored onto silica-coated gold nanorods (AuNR) with retained local surface plasmon resonance (LSPR). Independent LSPR and singlet oxygen production of anchored ZnPc enhance the photothermal and photodynamic efficacy of the obtained AuNR-Si-ZnPc under NIR light excitation. AuNR-Si-ZnPc was further grafted with hyaluronic acid (HA). Since HA has selective targeting capability to CD44 antigens, the final hybrid could target cancer cells directly for synergistic photothermal and photodynamic therapy.

Natural Myocardial ECM Patch Drives Cardiac Progenitor Based Restoration Even After Scarring

Acta Biomaterialia. Oct, 2016  |  Pubmed ID: 27545814

To evaluate the regenerative capacity of non-supplemented and bioactive patches made of decellularized porcine cardiac extracellular matrix (pcECM) and characterize the biological key factors involved in possible cardiac function (CF) restoration following acute and 8weeks chronic MI.

Bioprinting and Differentiation of Stem Cells

Molecules (Basel, Switzerland). Sep, 2016  |  Pubmed ID: 27617991

The 3D bioprinting of stem cells directly into scaffolds offers great potential for the development of regenerative therapies; in particular for the fabrication of organ and tissue substitutes. For this to be achieved; the lineage fate of bioprinted stem cell must be controllable. Bioprinting can be neutral; allowing culture conditions to trigger differentiation or alternatively; the technique can be designed to be stimulatory. Such factors as the particular bioprinting technique; bioink polymers; polymer cross-linking mechanism; bioink additives; and mechanical properties are considered. In addition; it is discussed that the stimulation of stem cell differentiation by bioprinting may lead to the remodeling and modification of the scaffold over time matching the concept of 4D bioprinting. The ability to tune bioprinting properties as an approach to fabricate stem cell bearing scaffolds and to also harness the benefits of the cells multipotency is of considerable relevance to the field of biomaterials and bioengineering.

Sustained Antibiotic-Eluting Intra-Ocular Lenses: A New Approach

PloS One. 2016  |  Pubmed ID: 27741256

Currently, infections following cataract surgery are not as effectively managed with antibiotic eye drops, which suffer from poor bioavailability of drug and low patient compliance. The ideal solution, which can help to overcome the issue of drug wastage and poor bioavailabilty, as well as the need for frequent applications (patient inconvenience), is a drug-eluting intraocular lens (IOL). We describe a novel approach to such a drug-eluting lens by using a peripheral IOL attachment as a drug depot to deliver antibiotics, Levofloxacin (LFX) or Moxifloxacin (MFX). In this work, drug was entrapped within a fully-degradable polymer, poly(L-lactide-co-ɛ-caprolactone) (PLC). The effects of drug loading and solvent type on drug release and film morphology were investigated using cast films. The study clearly demonstrated that a slower-evaporating solvent tetrahydrofuran (THF) resulted in a better surface morphology, as well as lower initial burst compared to dichloromethane (DCM), and hence, was better suited to developing a drug-eluting attachment with sustained release of drug. When attachments were fabricated with drugs at high loading percentages (20% and 25% in polymer), significant burst was observed compared to films: this is attributed to the higher surface-to-volume ratio of the attachments. When the levofloxacin (LFX) loading percentage was decreased to 3% and 5%, the attachments presented lower burst and sustained release with therapeutic efficacy. This work has demonstrated the potential of using an IOL attachment as a more efficacious anti-infective option compared to daily eye drops.

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