Mathematical modeling of degradation for bulk-erosive polymers: applications in tissue engineering scaffolds and drug delivery systems

The degradation of polymeric biomaterials, which are widely exploited in tissue engineering and drug delivery systems, has drawn significant attention in recent years. This paper aims to develop a mathematical model that combines stochastic hydrolysis and mass transport to simulate the polymeric degradation and erosion process. The hydrolysis reaction is modeled in a discrete fashion by a fundamental stochastic process and an additional autocatalytic effect induced by the local carboxylic acid concentration in terms of the continuous diffusion equation. Illustrative examples of microparticles and tissue scaffolds demonstrate the applicability of the model. It is found that diffusive transport plays a critical role in determining the degradation pathway, whilst autocatalysis makes the degradation size dependent. The modeling results show good agreement with experimental data in the literature, in which the hydrolysis rate, polymer architecture and matrix size actually work together to determine the characteristics of the degradation and erosion processes of bulk-erosive polymer devices. The proposed degradation model exhibits great potential for the design optimization of drug carriers and tissue scaffolds.     

Subcutaneous polymeric matrix system p(HEMA-BGA) for controlled release of an anticancer drug (5-fluorouracil). II: Release kinetics

A subcutaneous polymeric drug delivery system, which consists of a polymeric matrix of poly(hydroxyethyl methacrylate-bisglycol acrylate), was developed. 5-fluorouracil was used as the model anticancer drug. Polymer-drug beads with a diameter of 3 mm were prepared by low-temperature radiation polymerization. In order to modify the release rate, polymeric beads with different composition, drug loading and crosslinking density were obtained. The kinetics of drug release were described by the expression Mt/M infinity = ktn. The diffusional release exponent 'n', which was calculated from the release curves, indicated that the mechanism of drug release from the polymeric matrix is due to the anomalous (non-Fickian) type of diffusion.     

药物从溶蚀性高聚物基质内释放的双动边界问题

采用修正积分法，得到了药物从溶蚀性高聚物基质内释放的双动边界问题的近似解析解，给出了扩散边界和药物释放分数的计算公式及其在不同初装浓度和溶蚀速度下的计算结果，给出了药物满足零级释放的近似条件。这对研究药物从高聚物基质内的释放问题以及控释制剂的设计具有重要的意义。     

Molecular release from a polymeric microreservoir device: Influence of chemistry, polymer swelling, and loading on device performance

A polymeric microreservoir device for controlled-release drug delivery relies on the degradation of thin poly(lactic-co-glycolic acid) membranes that seal each reservoir to achieve pulsatile drug delivery. In vitro release studies in which the swelling of the reservoir membranes was measured indicate a correlation between the release times of various radiolabeled molecules from the devices and the time at which the maximum membrane swelling was observed. Varying the chemistry (lipophilicity/hydrophilicity) or molecular weight of the molecules loaded into the devices did not appear to affect the degree of membrane swelling that was observed, or the time at which the molecules were released from the devices. The amount of drug that was loaded into the reservoirs also did not appear to affect the observed release time of the drug from the device, a significant departure from the behavior of many matrix-type polymeric drug delivery systems.     

In vitro study of anticancer drug doxorubicin in PLGA-based microparticles

Doxorubicin (DOX), also known as adriamycin, is an anthracycline drug commonly used in cancer chemotherapy. Unfortunately, its therapeutic potential has been restricted by its dose limited cardiotoxicity and the resistance developed by the tumor cells to the molecule after some time of treatment. One way to overcome these problems is to encapsulate the drug in poly (D, L-lactide-co-glycolide) (PLGA) microparticles. This paper investigates the release characteristics of DOX from polymeric carriers fabricated using the spray-drying technique. The encapsulation efficiency, size and morphology of the various polymeric devices were also determined. In order to improve the release characteristics, Pluronic P105 (PLU) and poly (L-Lactide) (PLLA) are individually used in combination with PLGA. Finally, a cytotoxicity test was performed using Glioma C6 cancer cells to investigate the cytotoxicity of DOX delivered from PLGA microparticles. It has been found that the cytotoxicity of DOX to Glioma C6 cancer cells is enhanced when DOX is delivered from PLGA polymeric carrier.     

Influence of different parameters on drug release from hydrogel systems to a biomembrane model. Evaluation by differential scanning calorimetry technique

A comparative study on the drug release capacity of four water swellable polymeric systems was carried out by differential scanning calorimetry (DSC). The polymeric systems chosen were alpha,beta-polyaspartahydrazide (PAHy) crosslinked by glutaraldehyde (GLU) (PAHy-GLU) or by ethyleneglycoldiglycidylether (EGDGE), (PAHy-EGDGE), polyvinylalcohol (PVA) crosslinked by glutaraldehyde (PVA-GLU) and alpha,beta-poly(N-hydroxyethyl)-DL-aspartamide (PHEA) by gamma irradiation (PHEA-gamma matrices). The degree of crosslinking for PAHy-GLU, PAHy-EGDGE and PVA-GLU samples was about 0.4 and 0.8. These hydrogels were characterized as free of drugs and were loaded with diflunisal (DFN) (approximately 2.5% w/w). Diflunisal, a non-steroidal anti-inflammatory drug, has been chosen as a model drug to be incorporated into polymeric matrices to follow the release processes of a drug from these hydrogels to a model membrane made by unilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC). Differential scanning calorimetry appears to be a suitable technique to follow the transfer kinetics of the drug from the controlled release system to the biomembrane model. The drug releases from all the considered polymeric hydrogels, were compared with the release observed from the drug solid form by examining the effects on the thermotropic behaviour of DPPC unilamellar vesicles. The release kinetics of the drug from hydrogels were followed at 25, 37 and 50 degrees C to evidence the influence of temperature on the drug release and on the successive transfer to biological membrane model. Particularly, it appears evident that the total amount of drug transferred and the release rate are affected by the polymer crosslinking degree (it increases with crosslinking decrease) as well as by the nature of crosslinking agent. In fact, the drug release profiles from PAHy-GLU samples are more differentiated than those from PAHy-EGDGE. The effect of parameters correlating with the properties of starting polymer, such as water-affinity, crystallinity, glass-to-rubber transition temperature and affinity towards drug molecules, has been also evaluated.     

Fabrication of multi-layered biodegradable drug delivery device based on micro-structuring of PLGA polymers

A programmable and biodegradable drug delivery device is desirable when a drug needs to be administered locally. While most local drug delivery devices made of biodegradable polymers relied on the degradation of the polymers, the degradation-based release control is often limited by the property of the polymers. Thus, we propose micro-geometry as an alternative measure of controlling drug release. The proposed devices consist of three functional layers: diffusion control layer via micro-orifices, diffusion layer, and drug reservoir layers. A micro-fabrication technology was used to shape an array of micro-orifices and micro-cavities in 85/15PLGA layers. A thin layer of fast degrading 50/50PLGA was placed as the diffusion layer between the 85/15PLGA layers to prevent any burst-type release. To modulate the release of the devices, the dimension and location of the micro-orifices were varied and the responding in vitro release response of tetracycline was monitored over 2 weeks. The release response to the different micro-geometry was prominent and further analyzed by FEM simulation. Comparison of the experiments to the simulated results identified that the variation of micro-geometry influenced also the volume-dependent degradation rate and induced the osmotic pressure.     

Biodegradable fumarate-based drug-delivery systems for ophthalmic applications

The function of a photocrosslinked poly(propylene fumarate) (PPF)/poly(N-vinyl pyrrolidone) (PVP) matrix for the sustained release of three ophthalmic model drugs, acetazolamide (AZ), dichlorphenamide (DP), and timolol maleate (TM), was investigated. The drugs differ in molecular weight and degree of dissociation in aqueous environments; both are parameters that significantly influence drug diffusivity. AZ, DP, and TM-loaded cylindrical rods (10 mm length, 0.6 mm diameter) were fabricated by photoinduced cross-copolymerization of PPF and N-vinyl pyrrolidone (NVP) in molds. The released amounts of AZ, DP, TM, and NVP were determined by high-performance liquid chromatography (HPLC). The effects of drug properties and loading on the release kinetics were investigated. The in vitro release of AZ, DP, and TM was well sustained from the polymer matrices over a period of approximately 210, 270, and 250 days, respectively. The release kinetics correlated with the HPLC retention profiles of the different drugs. Following a small initial burst release (<10%), a dual modality release controlled by diffusion and bulk erosion was found for all drugs. Drug release rates of up to 4 microg/day were reached. Matrix drug loading generally affected the extent of the burst release, release kinetics, as well as the matrix water content and matrix degradation that were determined gravimetrically. Microcomputed tomography was used to image structural and dimensional changes of the devices. A preliminary rabbit implantation study revealed promising ocular biocompatibility of drug-free PPF/PVP matrices. All results indicate the potential of photocrosslinked PPF-based matrices as polymeric carriers for long-term ophthalmic drug delivery.     

Modeling of degradation and drug release from a biodegradable stent coating

Biodegradable polymeric coatings on cardiovascular stents can be used for local delivery of therapeutic agents to diseased coronary arteries after stenting procedures. This can minimize the occurrence of clinically adverse events such as restenosis after stent implantation. A validated mathematical model can be a very important tool in the design and development of such coatings for drug delivery. The model should incorporate the important physicochemical processes responsible for the polymer degradation and drug release. Such a model can be used to study the effect of different coating parameters and configurations on the degradation and the release of the drug from the coating. In this paper, a simultaneous transport-reaction model predicting the degradation and release of the drug Everolimus from a polylactic acid (PLA) based stent coating is presented. The model has been validated using in vitro testing data and was further used to evaluate the influence of various parameters such as partitioning coefficient of water, autocatalytic effect of the lactic acid and structural change of the matrix, on the PLA degradation and drug release. The model can be used as a tool for predicting drug delivery from other coating configurations designed using the same polymer-drug combination. In addition, this modeling methodology has broader applications and can be used to develop mathematical models for predicting the degradation and drug release kinetics for other polymeric drug delivery systems.     

Hercon technology for transdermal delivery of drugs

The Hercon controlled drug delivery technology is based on a multi-layered laminated polymeric structure, in which a layer of vinyl chloride copolymer or terpolymer containing the drug is sandwiched between two or more layers of polymeric films. The drug is released from the device at a controlled rate by a process of diffusion through the reservoir and one of the outer layers, which can function as a rate controlling membrane. This basic technology has been successfully utilized for the development and commercialization of Nitroglycerin Transdermal System (NTS, Bolar Pharmaceutical Co., Inc). In vitro and in vivo investigations of transdermal delivery of different other drugs from the Hercon polymeric devices have indicated the feasibility of using this system to meet a variety of therapeutic needs.     

In vitro release of clomipramine HCl and buprenorphine HCl from poly adipic anhydride (PAA) and poly trimethylene carbonate (PTMC) blends

Controlled drug-delivery technology is concerned with the systematic release of a pharmaceutical agent to maintain a therapeutic level of the drug in the body for modulated and/or prolonged periods of time. This may be achieved by incorporating the therapeutic agent into a degradable polymer vehicle, which releases the agent continuously as the matrix erodes. In this study, poly trimethylene carbonate (PTMC), an aliphatic polycarbonate, and poly adipic anhydride (PAA), an aliphatic polyanhydride, were synthesized via melt condensation and ring-opening polymerization of trimethylene carbonate and adipic acid, respectively. The release of clomipramine HCl and buprenorphine HCl from discs prepared with the use of PTMC-PAA blends in phosphate buffer (pH 7.4) are also described. Clomipramine HCl and buprenorphine HCl were both used as hydrophilic drug models. Theoretical treatment of the data with the Peppas model revealed that release of clomipramine HCl (5%) in devices containing 70% PTMC or more followed a Fickian diffusion model. However, the releases of buprenorphine HCl (5%) in the same devices were anomalous. For devices containing 50% and more PAA, surface erosion may play a significant role in the release of both molecules.     

Size and temperature effects on poly(lactic-co-glycolic acid) degradation and microreservoir device performance

The component materials of controlled-release drug delivery systems are often selected based on their degradation rates. The release time of a drug from a system will strongly depend on the degradation rates of the component polymers. We have observed that some poly(lactic-co-glycolic acid) polymers (PLGA) exhibit degradation rates that depend on the size of the polymer object and the temperature of the surrounding environment. In vitro degradation studies of four different PLGA polymers showed that 150 microm thick membranes degraded more rapidly than 50 microm thick membranes, as characterized by gel permeation chromatography and mass loss measurements. Faster degradation was observed at 37 degrees C than 25 degrees C, and when the saline media was not refreshed. A biodegradable polymeric microreservoir device that we have developed relies on the degradation of polymeric membranes to deliver pulses of molecules from reservoirs on the device. Earlier molecular release was seen from devices having thicker PLGA membranes. Comparison of an in vitro release study from these devices with the degradation study suggests that reservoir membranes rupture and drug release occurs when a membrane threshold molecular weight of 5000-15000 is reached.     

Preparation,characterization, and in vitro drug release behavior of glutathione-sensitive long-circulation micelles based on polyethylene glycol prodrug

In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH)-sensitive strategy is based on a Michael addition–elimination reaction, that is the amphiphilic polymeric prodrug which contains α, β-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile – glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 ± 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days. In vitro drug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV–vis spectrophotometer. In vitro macrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs.     

Characterization of a poly-epsilon-caprolactone polymeric drug delivery device built by selective laser sintering

Selective Laser Sintering (SLS), an established Rapid Prototyping (RP) process, is investigated for building controlled drug delivery devices (DDD). The drug and its matrix in a powder form were first mixed mechanically before being sintered on the SLS. Each cylindrical DDD is designed with a number of concentric rings separated from each other by a characteristic 'wall' created by the laser of the SLS. These rings act as diffusion obstacles to control the rate of release. Poly-epsilon-caprolactone (PCL) was used as the matrix and Methylene Blue (MB) as the drug model. Samples were built, characterized and tested for homogeneity using Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), and Fourier Transform Infrared Spectrophotometry (FTIR). Experimental results show that the matrices fabricated are not affected by sintering and the polymer and drug model are evenly distributed throughout the matrix. The initial burst effect has been reduced by the increase of the numbers of rings. The linear curve using the Higuchi equation confirmed that the DDD matrix release profile is by diffusion. These results show that the DDD matrix design has promising potential for application in controlled release drug delivery.     

Mechanical and diffusive properties of homogeneous alginate gels in form of particles and cylinders

In this study, alginate polymers are used to get homogeneous cylindrical or spherical gels. MRI techniques are employed to study homogeneity of these gels. Four different alginates are used and, for each one, five different concentrations for mechanical tests and three different concentrations for release tests are studied. Mechanical tests are performed to get gels' linear viscoelasticity region and then to evaluate their crosslink density in relation to polymer concentration. Afterwards, three model molecules (theophylline, vitamin B(12), and myoglobin) are loaded within gels to study the release kinetics in water from both cylindrical and spherical gels. Diffusion coefficients calculated from these experiments are then used to estimate the polymeric network mesh wideness. This work shows how crosslink density increases with polymer concentration regardless of the alginate type considered. In addition, while vitamin B(12) diffusion coefficient is inversely proportional to crosslink density, myoglobin is too large to diffuse through the polymeric network, whatever the alginate type and polymer concentration. At the same time, theophylline is too small to be sensibly affected by increasing the polymeric network crosslink density. Finally, MRI analysis and vitamin B(12) diffusion coefficient values prove that, structurally speaking, cylinders and spheres are similar and homogeneous.     

Design of a Self-Regulated Drug Delivery Device

Most conventional drug delivery systems are based on polymers or lipid vesicles. These chemically synthesized materials can be designed to be biocompatible and have good functionality, but they often lack well-defined properties, due to an inherent size and structure distribution resulting from chemical synthesis. On the other hand, micro-fabrication technology developed for microelectronic applications is capable of mechanically creating devices with more precisely defined features, in a size range similar to polymeric and lipid materials. In this paper, we describe the design of a self-regulated drug delivery device based on the integration of both mechanical and chemical methods. In this device, a constant release rate can be achieved by carefully designing the shape of the drug reservoir, while a pH-sensitive hydrogel switch is used to regulate the drug release.     

Multistructured Nanogel‐Based Networks Formed from Interfacial Redox Polymerizations for Modulating Small Molecule Release

Uniform, 3D nanogel‐based coatings are generated on polymeric substrates using an interfacial redox polymerization. Diffusion of a reducing agent from a core material into a solution of acrylate‐functionalized nanogels and an oxidizer generates free radicals that initiate nanogel crosslinking selectively at the gel surface. Coating thickness is controlled between 20 and 150 µm by varying reaction time and initiator concentration. Controlling the structure of the final nanogel‐based coating is demonstrated to predictably change the diffusion coefficient of a small molecule drug loaded into the core material. Multidrug release from the coating and the core is demonstrated with model dyes. This study showcases the ability to design multifunctional networks for controlled release using a simple, mild coating procedure.     

The pre-clinical assessment of rapamycin-eluting, durable polymer-free stent coating concepts

All four currently FDA-approved drug-eluting stents (DESs) contain a durable polymeric coating which can negatively impact vascular healing processes and eventually lead to adverse cardiac events. Aim of this study was the pre-clinical assessment of two novel rapamycin-eluting stent (RES) coating technologies that abstain from use of a durable polymer. Two distinctive RES coating technologies were evaluated in vitro and in the porcine coronary artery stent model. The R-poly(S) stent platform elutes rapamycin from a biodegradable polymer that is top coated with the resin shellac to minimize the amount of polymer. The R-pro(S) stent platform allows dual drug release of rapamycin and probucol, blended by shellac. HPLC-based determination of pharmacokinetics indicated drug release for more than 28 days. At 30 days, neointimal formation was found to be significantly decreased for both DESs compared to bare-metal stents. Assessment of vascular healing revealed absence of increased inflammation in both DESs, which is commonly observed in DES with non-erodible polymeric coating. In conclusion, the pre-clinical assessment of RESs with resin-based or dual drug coating indicated an adequate efficacy profile as well as a beneficial effect for vascular healing processes. These results encourage the transfer of these technologies to clinical evaluation.     

Biocompatibility of implantable synthetic polymeric drug carriers: focus on brain biocompatibility

Numerous polymeric biomaterials are implanted each year in human bodies. Among them, drug delivery devices are potent novel powerful therapeutics for diseases which lack efficient treatments. Controlled release systems are in direct and sustained contact with the tissues, and some of them degrade in situ. Thus, both the material itself and its degradation products must be devoid of toxicity. The knowledge and understanding of the criteria and mechanisms determining the biocompatibility of biomaterials are therefore of great importance. The classical tissue response to a foreign material leads to the encapsulation of the implant, which may impair the drug diffusion in the surrounding tissue and/or cause implant failure. This tissue response depends on different factors, especially on the implantation site. Indeed, several organs possess a particular immunological status, which may reduce the inflammatory and immune reactions. Among them, the central nervous system is of particular interest, since many pathologies still need curative treatments. This review describes the classical foreign body reaction and exposes the particularities of the central nervous system response. The recent in vivo biocompatibility studies of implanted synthetic polymeric drug carriers are summarized in order to illustrate the behavior of different classes of polymers and the methodologies used to evaluate their tolerance.