PLGA Implants Research Articles

Cowpea Mosaic Virus Nanoparticle Vaccine Candidates Displaying Peptide Epitopes Can Neutralize the Severe Acute Respiratory Syndrome Coronavirus.

The development of vaccines against coronaviruses has focused on the spike (S) protein, which is required for the recognition of host-cell receptors and thus elicits neutralizing antibodies. Targeting conserved epitopes on the S protein offers the potential for pan-beta-coronavirus vaccines that could prevent future pandemics. We displayed five B-cell epitopes, originally identified in the convalescent sera from recovered severe acute respiratory syndrome (SARS) patients, on the surface of the cowpea mosaic virus (CPMV) and evaluated these formulations as vaccines. Prime-boost immunization of mice with three of these candidate vaccines, CPMV-988, CPMV-1173, and CPMV-1209, elicited high antibody titers that neutralized the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro and showed an early Th1-biased profile (2–4 weeks) transitioning to a slightly Th2-biased profile just after the second boost (6 weeks). A pentavalent slow-release implant comprising all five peptides displayed on the CPMV elicited anti-S protein and epitope-specific antibody titers, albeit at a lower magnitude compared to the soluble formulations. While the CPMV remained intact when released from the PLGA implants, processing results in loss of RNA, which acts as an adjuvant. Loss of RNA may be a reason for the lower efficacy of the implants. Finally, although the three epitopes (988, 1173, and 1209) that were found to be neutralizing the SARS-CoV were 100% identical to the SARS-CoV-2, none of the vaccine candidates neutralized the SARS-CoV-2 in vitro suggesting differences in the natural epitope perhaps caused by conformational changes or the presence of N-linked glycans. While a cross-protective vaccine candidate was not developed, a multivalent SARS vaccine was developed. The technology discussed here is a versatile vaccination platform that can be pivoted toward other diseases and applications that are not limited to infectious diseases.

Spiramyin-loaded PLGA implants for the treatment of ocular toxoplasmosis: development, characterization, biocompatibility, and anti-toxoplasma activity.

Ocular toxoplasmosis is the major cause of infectious posterior uveitis worldwide, inducing visual field defect and/or blindness. Despite the severity of this disease, an effective treatment is still lacking. In this study, spiramycin-loaded PLGA implants were developed aiming at the treatment of ocular toxoplasmosis. Implants were manufactured by a hot-molding technique, characterized by Fourier Transform Infrared Spectroscopy, X-Ray Diffraction, Differential Scanning Calorimetry, Scanning Electron Microscopy; evaluated in terms of ocular biocompatibility by immunofluorescence, flow cytometry, cell migration, Hen's egg test-chorioallantoic membrane (HET-CAM) irritation test; and investigated in terms of in vitro efficacy against Toxoplasma gondii . Characterization techniques indicated that spiramycin was dispersed into the polymeric chains and both substances preserved their physical structures in implants. The HET-CAM test indicated that implants did not induce hemorrhage or coagulation, being non-irritant to the CAM. ARPE-19 cells showed viability by MTT assay, and normality in cell cycle kinetics and morphology, without stimulating cell death by apoptosis. Finally, they were highly effective against intracellular parasites without inducing human retinal pigment epithelial cell death. In conclusion, spiramycin-loaded PLGA implants represent a promising therapeutic alternative for the local treatment of ocular toxoplasmosis.

Microimaging of a novel intracochlear drug delivery device in combination with cochlear implants in the human inner ear

The effective delivery of drugs to the inner ear is still an unmet medical need. Local controlled drug delivery to this sensory organ is challenging due to its location in the petrous bone, small volume, tight barriers, and high vulnerability. Local intracochlear delivery of drugs would overcome the limitations of intratympanic (extracochlear) and systemic drug application. The requirements for such a delivery system include small size, appropriate flexibility, and biodegradability. We have developed biodegradable PLGA-based implants for controlled intracochlear drug release that can also be used in combination with cochlear implants (CIs), which are implantable neurosensory prosthesis for hearing rehabilitation. The drug carrier system was tested for implantation in the human inner ear in 11 human temporal bones. In five of the temporal bones, CI arrays from different manufacturers were implanted before insertion of the biodegradable PLGA implants. The drug carrier system and CI arrays were implanted into the scala tympani through the round window. Implanted temporal bones were evaluated by ultra-high-resolution computed tomography (µ-CT) to illustrate the position of implanted electrode carriers and the drug carrier system. The µ-CT measurements revealed the feasibility of implanting the PLGA implants into the scala tympani of the human inner ear and co-administration of the biodegradable PLGA implant with a CI array.Graphical abstract

The Effect of Diclofenac Sodium-Loaded PLGA Rods on Bone Healing and Inflammation: A Histological and Histomorphometric Study in the Femur of Rats.

Implants made of poly(lactide-co-glycolide) (PLGA) are biodegradable and frequently provoke foreign body reactions (FBR) in the host tissue. In order to modulate the inflammatory response of the host tissue, PLGA implants can be loaded with anti-inflammatory drugs. The aim of this study was to analyze the impact of PLGA 80/20 rods loaded with the diclofenac sodium (DS) on local tissue reactions in the femur of rats. Special emphasis was put on bone regeneration and the presence of multinucleated giant cells (MGCs) associated with FBR. PLGA 80/20 alone and PLGA 80/20 combined with DS was extruded into rods. PLGA rods loaded with DS (PLGA+DS) were implanted into the femora of 18 rats. Eighteen control rats received unloaded PLGA rods. The follow-up period was of 3, 6 and 12 weeks. Each group comprised of six rats. Peri-implant tissue reactions were histologically and histomorphometrically evaluated. The implantation of PLGA and PLGA+DS8 rods induced the formation of a layer of newly formed bone islands parallel to the contour of the implants. PLGA+DS rods tended to reduce the presence of multi-nucleated giant cells (MGCs) at the implant surface. Although it is known that the systemic administration of DS is associated with compromised bone healing, the local release of DS via PLGA rods did not have negative effects on bone regeneration in the femora of rats throughout 12 weeks.

Drug-Eluting Biodegradable Implants for the Sustained Release of Bisphosphonates.

Despite being one of the first-line treatments for osteoporosis, the bisphosphonate drug class exhibits an extremely low oral bioavailability (<1%) due to poor absorption from the gastrointestinal tract. To overcome this, and to explore the potential for sustained drug release, bioerodible poly(lactic acid) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) implants loaded with the bisphosphonate alendronate sodium (ALN) were prepared via hot-melt extrusion. The rate of drug release in vitro was modulated by tailoring the ratio of lactide to glycolide in the polymer and by altering the ALN-loading of the implants. All investigated implants exhibited sustained ALN release in vitro between 25 to 130 days, where implants of greater glycolide composition and higher ALN-loadings released ALN more rapidly. All PLGA implants demonstrated a sigmoidal release profile, characterised by an initial surface dissolution phase, followed by a period of zero-order drug diffusion, then relaxation or erosion of the polymer chains that caused accelerated release over the subsequent days. Contrastingly, the PLA implants demonstrated a logarithmic release profile, characterised by a gradual decrease in ALN release over time.

Silica particles incorporated into PLGA-based in situ-forming implants exploit the dual advantage of sustained release and particulate delivery

Poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants are well-established drug delivery systems for controlled drug release over weeks up to months. To prevent initial burst release, which is still a major issue associated with PLGA-based implants, drugs attached to particulate carriers have been encapsulated. Unfortunately, former studies only investigated the resulting release of the soluble drugs and hence missed the potential offered by particulate drug release. In this study, we developed a system capable of releasing functional drug-carrying particles over a prolonged time. First, we evaluated the feasibility of our approach by encapsulating silica particles of different sizes (500 nm and 1 μm) and surface properties (OH or NH2 groups) into in situ-forming PLGA implants. In this way, we achieved sustained release of particles over periods ranging from 30 to 70 days. OH-carrying particles were released much more quickly when compared to NH2-modified particles. We demonstrated that the underlying release mechanisms involve size-dependent diffusion and polymer-particle interactions. Second, particles that carried covalently-attached ovalbumin (OVA) on their surfaces were incorporated into the implant. We demonstrated that OVA was released in association with the particles as functional entities over a period of 30 days. The released particle-drug conjugates maintained their colloidal stability and were efficiently taken up by antigen presenting cells. This system consisting of particles incorporated into PLGA-based in situ-forming implants offers the dual advantage of sustained and particulate release of drugs as a functional unit and has potential for future use in many applications, particularly in single-dose vaccines.

Beneficial Therapeutic Approach of Acellular PLGA Implants Coupled With Rehabilitation Exercise for Osteochondral Repair: A Proof of Concept Study in a Minipig Model

Background: Osteochondral (OC) repair presents a significant challenge to clinicians. However, whether the use of acellular spongy poly(lactic-co-glycolic acid) (PLGA) scaffolding plus treadmill exercise as a rehabilitation program regenerates OC defects in a large-animal model has yet to be determined. Hypothesis: PLGA scaffolding plus treadmill exercise may offer improved OC repair for both high and low weightbearing regions in a minipig model. Study Design: Controlled laboratory study. Methods: A total of 9 mature minipigs (18 knees) were randomly divided into the treadmill exercise (TRE) group or sedentary (SED) group. All pigs received critically sized OC defects in a higher weightbearing region of the medial condyle and a lower weightbearing region of the trochlear groove. In each minipig, a PLGA scaffold was placed in the defect of the right knee (PLGA subgroup), and the defect of the left knee was untreated (empty defect [ED] subgroup). The TRE group performed exercises in 3 phases: warm-up, 3 km/h for 5 minutes; main exercise, 4 km/h for 20 minutes; and cool-down, 3 km/h for 5 minutes. The total duration was about 30 minutes whenever possible. The SED group was allowed free cage activity. Results: At 6 months, the TRE-PLGA group showed the highest gross morphology scores and regenerated a smooth articular surface covered with new hyaline-like tissue, while the defects of the other groups remained and contained nontransparent tissue. Histologically, the TRE-PLGA group also revealed sound OC integration, chondrocyte-like cells embedded in lacunae, abundant glycosaminoglycans, a sound collagen structure, and modest inflammatory cells with an inflammatory response (ie, tumor necrosis factor–α, interleukin-6). In addition, in the medial condyle region, the TRE-PLGA group (31.80 ± 3.03) had the highest total histological scores (TRE-ED: 20.20 ± 5.76; SED-PLGA: 10.25 ± 6.24; SED-ED: 11.75 ± 6.50; P = .004). In the trochlear groove region, the TRE-PLGA group (30.20 ± 6.42) displayed significantly higher total histological scores (TRE-ED: 19.60 ± 7.00; SED-PLGA: 10.00 ± 5.42; SED-ED: 11.25 ± 5.25; P = .006). In contrast, the SED-PLGA and SED-ED groups revealed an irregular surface with abrasion, fibrotic tissue with an empty void and inflammatory cells, disorganized collagen fibers, and less glycosaminoglycan deposition. Micro–computed tomography analysis revealed that the TRE-PLGA group had integrated OC interfaces with continued remodeling in the subchondral bone. Furthermore, comparing the 2 defect regions, no statistically significant differences in cartilage regeneration were detected, indicating the suitability of this regenerative approach for both high and low weightbearing regions. Conclusion: Implanting an acellular PLGA scaffold plus treadmill exercise promoted articular cartilage regeneration for both high and low weightbearing regions in minipigs. Clinical Relevance: This study suggests the use of a cell-free porous PLGA scaffold and treadmill exercise rehabilitation as an alternative therapeutic strategy for OC repair in a large-animal knee joint model. This combined effect may pave the way for biomaterials and exercise regimens in the application of OC repair.

Microencapsulation of amorphous solid dispersions of fenretinide enhances drug solubility and release from PLGA in vitro and in vivo.

The purpose of this study was to develop solid dispersions of fenretinide(4HPR), incorporate them into poly(lactic-co-glycolic)(PLGA) millicylindrical implants, and evaluate the resulting implants in vitro and in vivo for future applications in oral cancer chemoprevention. Due to the extreme hydrophobicity of 4HPR, 4HPR-polyvinylpyrrolidone (PVP) amorphous solid dispersions(ASDs) were prepared for solubility enhancement. The optimal PVP-4HPR ratio of 9/1(w/w) provided a 50-fold solubility enhancement in aqueous media, which was sustained over 1week. PVP-4HPR ASD particles were loaded into PLGA millicylinders and drug release was evaluated in vitro in PBST and in vivo by recovery from subcutaneous injection in rats. While initial formulations of PLGA PVP-4HPR millicylinders only released 10% 4HPR in vitro after 28days, addition of the plasticizer triethyl-o-acetyl-citrate(TEAC) into PVP-4HPR ASDs resulted in a 5.6-fold total increase in drug release. Remarkably, the TEAC-PVP-4HPR PLGA implants demonstrated slow, continuous, and nearly complete release over 1month in vivo compared to a 25% release for our previously reported formulation incorporating solubilizers and pore-forming agents. Hence, a combination of PLGA plasticizer and ASD formation provides an avenue for long-term controlled release in vivo for the exceptionally difficult drug to formulate, 4HPR, and a suitable formulation for future evaluation in rodent models of oral cancer.

Size-Exclusive Nanoporous Biodegradable PLGA Capsules for Drug Delivery Implants and In Vivo Stability in the Posterior Segment.

The current standard of care for posterior segment eye diseases, such as neovascular age-related macular degeneration, diabetic macular edema, is frequent intravitreal injections or sustained-release drug implants. Intravitreal injections have a low incidence of serious complications such as retinal detachment, endophthalmitis, iatrogenic traumatic cataract, or iridocyclitis and injection-site reactions. However, there is a significant burden to the patient, the patient's family, and the health system because current intravitreal therapies require between every 4 and 12 week administration over many years. Drug implants have side effects due to the burst release of the drugs, and their release cannot be easily controlled after implantation. We have developed a size-exclusive nanoporous biodegradable PLGA capsule for dosage-controllable drug delivery implants. We have optimized the nanoporous structure by tuning the ratio between porogen and high molecular weight PLGA and tested the stability against passive leakage of the liposomal drug (1-2 μm) and the safety in vivo rabbit eyes for 6 months. Our results suggest that PLGA implants made of the nanoporous PLGA sheet can selectively release drug molecules, keeping the liposomal drug inside. In addition, the implant was biocompatible, causing no inflammation and foreign body response when implanted for 6 months. Overall, the implant shows great potential for on-demand dose-controllable drug release applications.

Nanoparticles for regenerative medicine.

Nanoparticles for regenerative medicine.

In-situ forming PLGA implants: How additives affect swelling and drug release

The aim of this study was to investigate the impact of the addition of very different types of additives on the key features of in-situ forming implants based on poly(D,L-lactic-co-glycolic acid) (PLGA, Resomer RG 502H) loaded with dexamethasone. All ingredients were dissolved in N-methyl-pyrrolidone (NMP), the implants formed upon solvent exchange. Crosslinked poly(acrylic acid) (Carbopol), poly(ethylene glycol) (PEG 400), hydroxypropyl methylcellulose (HPMC K100, HPMC E15), stearic acid and acetyltributyl citrate (ATBC) were studied as additives, in concentrations up to 5% (except for ATBC: up to 20%). Dynamic changes in the implants' wet mass, pH of the release medium, NMP leaching as well as dexamethasone release were monitored upon exposure to phosphate buffer pH 7.4. Also the implants’ inner and outer morphology was studied, using optical and scanning electron microscopy. Interestingly, the addition of the very different types of additives partially substantially altered the morphology and swelling kinetics of the investigated in-situ forming PLGA implants, whereas the impact on dexamethasone release was rather limited in all cases. Generally, the release rate slightly increased in the presence of the additives, only in the case of ATBC it slightly decreased. The overall limited effect on drug release might at least partially be attributed to the fact that: (i) water-soluble additives might rapidly leach out into the aqueous release medium during implant formation and/or promote implant swelling, and (ii) lipophilic additives might induce phase separation.

Coloring of PLGA implants to better understand the underlying drug release mechanisms.

Different dyes and a colored vitamin (riboflavin) were used to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA)-based implants. The latter were prepared by hot melt extrusion (HME) or formed in-situ, upon solvent exchange when injecting a PLGA solution in N-methyl-pyrrolidone (NMP) into phosphate buffer pH 7.4. Methylene blue was used as water-soluble dye to stain the release medium, riboflavin as a yellow, water-soluble "model drug", and Sudan-III-red as poorly water-soluble dye, incorporated in the implant. In the case of pre-formed HME implants, the "orchestrating" role of polymer swelling for the control of drug release could be visualized: At early time points, only limited amounts of water penetrate into the system, insufficient for noteworthy drug dissolution and diffusion. However, bulk erosion starts, and once a critical polymer molecular weight threshold value is reached, substantial implant swelling sets on: Large amounts of water come in and allow for significant drug dissolution and diffusion. In the case of in-situ forming implants, the importance of the composition of the liquid formulation for the resulting inner implant structure could be visualized. The latter affects the rate and extent at which water penetrates into the system and, thus, the resulting drug release rate.

Polymer degradation induced drug precipitation in PLGA implants – Why less is sometimes more

Nifedipine and nicardipine loaded PLGA extrudates have a great potential to prevent cerebral vasospasms after subarachnoid hemorrhage or surgical clipping of aneurysm. A constant release over approx. two weeks is desired. Although in vivo studies on humans have been reported, there is limited knowledge about the release kinetics and the underlying mechanisms. Therefore, nifedipine and nicardipine loaded PLGA implants with different drug loads were manufactured by extrusion and investigated. In addition to the measurements of the release kinetics, GPC, DSC, X-ray diffraction and light microscopic investigations were performed for a detailed characterization. The water uptake and polymer erosion studies showed an initial lag phase of 5–7 days and an acceleration of both processes thereafter. With 5% loaded implants a higher drug release compared to 10% drug loaded polymers could be achieved and not only the relative amount of drug release (% of loaded drug), but surprisingly also the absolute amount of the released drug increased. The drugs were initially in an amorphous state. For nifedipine, formation of drug crystals with time has been observed by light microscopy and X-ray diffraction. The analysis of the drug content in the degrading polymer showed a very large increase from 10% to about 20% (nifedipine) and over 50% (nicardipine). In contrast, no or only a moderate increase of the drug content occurred for initially 5% loaded polymer implants. We postulate that water penetration and polymer degradation induced changes of the microenvironment lead to supersaturated systems. A supersaturated state is faster reached for polymers with higher drug load and therefore, drug precipitation takes place at earlier time points.As a result, drug release might be incomplete for poorly soluble drugs and paradoxically, the total amount of drug release might be higher for systems with a lower drug load. Drug release is initially controlled by the PLGA matrix, but later by the dissolution kinetics of the precipitated drug which are very slow for poorly soluble drugs according to the Noyes-Whitney equation.

Local penetration of doxorubicin via intrahepatic implantation of PLGA based doxorubicin-loaded implants

Doxorubicin (DOX) is widely used in the chemotherapy of a wide range of cancers. However, intravenous administration of DOX causes toxicity to most major organs which limits its clinical application. DOX-loaded drug delivery system could provide a continuous sustained-release of drugs and enables high drug concentrations at the target site, while reducing systemic toxicity. Additionally, local chemotherapy with DOX may be a promising approach for lowering post-surgical recurrence of cancer. In this study, the sustained-release DOX-loaded implants were prepared by melt-molding method. The implants were characterized with regards to drug content uniformity, micromorphology and drug release profiles. Furthermore, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) analyses were carried out to investigate the drug-excipient compatibility. To determine the local penetration of DOX in liver, the minipigs received intrahepatic implantation of DOX-loaded implants by abdominal surgery. UPLC-MS/MS method was used to detect the concentration of DOX in liver tissues. Our results suggested that DOX-loaded implants delivered high doses of drug at the implantation site for a prolonged period and provided valuable information for the future clinical applications of the DOX-loaded implants.

A Computational Model for Drug Release from PLGA Implant.

Due to the relative ease of producing nanofibers with a core–shell structure, emulsion electrospinning has been investigated intensively in making nanofibrous drug delivery systems for controlled and sustained release. Predictions of drug release rates from the poly (d,l-lactic-co-glycolic acid) (PLGA) produced via emulsion electrospinning can be a very difficult task due to the complexity of the system. A computational finite element methodology was used to calculate the diffusion mass transport of Rhodamine B (fluorescent drug model). Degradation effects and hydrophobicity (partitioning phenomenon) at the fiber/surrounding interface were included in the models. The results are validated by experiments where electrospun PLGA nanofiber mats with different contents were used. A new approach to three-dimensional (3D) modeling of nanofibers is presented in this work. The authors have introduced two original models for diffusive drug release from nanofibers to the 3D surrounding medium discretized by continuum 3D finite elements: (1) A model with simple radial one-dimensional (1D) finite elements, and (2) a model consisting of composite smeared finite elements (CSFEs). Numerical solutions, compared to experiments, demonstrate that both computational models provide accurate predictions of the diffusion process and can therefore serve as efficient tools for describing transport inside a polymer fiber network and drug release to the surrounding porous medium.

Toxicity and in vivo release profile of sirolimus from implants into the vitreous of rabbits' eyes.

To assess the in vivo release profile and the retinal toxicity of a poly (lactic-co-glycolic acid) (PLGA) sustained-release sirolimus (SRL) intravitreal implant in normal rabbit eyes. PLGA intravitreal implants containing or not SRL were prepared, and the viability of ARPE-19 and hES-RPE human retinal cell lines was examined after 24 and 72h of exposure to implants. New Zealand rabbits were randomly divided into two groups that received intravitreal implants containing or not SRL. At each time point (1-8weeks), four animals from the SRL group were euthanized, the vitreous was collected, and drug concentration was calculated. Clinical evaluation of the eyes was performed weekly for 8weeks after administration. Electroretinography (ERG) was recorded in other eight animals, four for each group, at baseline and at 24h, 1, 4, 6, and 8weeks after the injection. ERG was carried out using scotopic and photopic protocols. The safety of the implants was assessed using statistical analysis of the ERG parameters (a and b waves, a and b implicit time, B/A ratio, oscillatory potential, and Naka-Rushton analysis) comparing the functional integrity of the retina between the PLGA and SRL-PLGA groups. After the last electrophysiological assessment, the rabbits were euthanized and retinal histopathology was realized. After 24 and 72h of incubation with PLGA or SRL-PLGA implants, ARPE-19 and hES-RPE cells showed viability over 70%. The maximum concentration of SRL (199.8ng/mL) released from the device occurred within 4weeks. No toxic effects of the implants or increase in the intraocular pressure was observed through clinical evaluation of the eye. ERG responses showed no significant difference between the eyes that received PLGA or SRL-PLGA implants at baseline and throughout the 8weeks of follow-up. No remarkable difference in retinal histopathology was detected in rabbit eyes treated with PLGA or SRL-PLGA implants. Intravitreal PLGA or SRL-PLGA implants caused no significant reduction in cell viability and showed no evident toxic effect on the function or structure of the retina of the animals. SRL was released from PLGA implant after application in the vitreous of rabbits during 8weeks.

Fracture Healing and Bone Remodeling With Human Standard-Sized Magnesium Versus Polylactide–Co-Glycolide Plate and Screw Systems Using a Mini-Swine Craniomaxillofacial Osteotomy Fixation Model

This study compared the degradation profile, safety, and efficacy of bioresorbable magnesium alloy and polylactide-co-glycolide (PLGA) polymer osteosynthesis systems for the treatment of fractures in a load-sharing maxillofacial environment using a new mini-swine fracture fixation model. Two types of clinically relevant situations were evaluated in 5 Yucatan miniature pigs. Defined porcine midface osteotomies of the supraorbital rim and zygoma were created and fixed with either a coated magnesium (test animals) or PLGA plate and screw osteosynthesis system (control animals). After surgery, the mini-pigs were able to recover for either 1 or 9months with continuous invivo post-implantation monitoring. Standardized computed tomography (CT) imaging was taken immediately postoperatively and at termination for all animals. The 9-month cohort also underwent CT at 2, 4, and 6months after surgery. At necropsy, osteotomy sites and bone-implant units were harvested, and healing was evaluated by micro-CT, histopathology, and histomorphometry. After clinical and radiologic follow-up examination, all fracture sites healed well for both the magnesium and polymer groups regardless of time point. Complete bone union and gradually disappearing osteotomy lines were observed across all implantation sites, with no major consistency change in periprosthetic soft tissue or in soft tissue calcification. Macroscopic and microscopic examination showed no negative influence of gas formation observed with magnesium during the healing process. Histopathologic analysis showed similar fracture healing outcomes for both plating systems with good biocompatibility as evidenced by a minimal or mild tissue reaction. This study confirms that WE43 magnesium alloy exhibited excellent fracture healing properties before its full degradation without causing any substantial inflammatory reactions in a long-term porcine model.Compared with PLGA implants, magnesium represents a promising new biomaterial with reduced implant sizes and improved mechanical properties to support fracture healing in a load-sharing environment.

Influence of the test method on in vitro drug release from intravitreal model implants containing dexamethasone or fluorescein sodium in poly (d,l-lactide-co-glycolide) or polycaprolactone

Sustained intravitreal dexamethasone (DX) administration with the FDA and EMA approved Ozurdex® implant is indicated for the treatment of macular edema and non-infectious uveitis. Since drug release after intravitreal application cannot be determined in vivo in human eyes, the characterization of drug release in vitro in addition to animal models is of great importance. The aim of this study was to provide information about the influence of the test method on the in vitro drug release from intravitreal model implants. The following test methods were used: a shaking incubator experiment in reagent tubes, the small volume USP apparatus 7, the Vitreous Model (VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS). Cylindrical model implants composed of DX and PLGA (poly (d,l-lactide-co-glycolide)) and additional polycaprolactone (PCL) implants containing fluorescein sodium (FS) as a model substance were produced by hot melt extrusion and were cut to a length of approximately 6 mm. Drug release was studied in ringer buffer pH 7.4 and in a modified polyacrylamide gel (PAAG) as vitreous substitute. In combination with the VM, the shape, the gel structure and a partial liquefaction (50%) were simulated in vitro.Swelling, disintegration, fragmentation, surface enlargement and changes in shape of the PLGA model implants were observed during the drug release study. We experienced that not each of the test methods and media were suitable for drug release studies of the PLGA implants. Marked differences in the release profiles were observed depending on the employed test method. These results emphasize the necessity to understand the underlying in vivo processes and to transfer the knowledge about the release determining factors into reliable in vitro test systems.

Concomitant monitoring of implant formation and drug release of in situ forming poly (lactide-co-glycolide acid) implants in a hydrogel matrix mimicking the subcutis using UV–vis imaging

For poly (lactide-co-glycolide acid) (PLGA)-based in situ forming implants, the rate of implant formation plays an important role in determining the overall drug release kinetics. Currently, in vitro techniques capable of characterizing the processes of drug release and implant formation at the same time are not available. A hydrogel-based in vitro experimental setup was recently developed requiring only microliter of formulation and forming a closed system potentially suitable for interfacing with various spectroscopic techniques. The aim of the present proof-of-concept study was to investigate the feasibility of concomitant UV imaging, Vis imaging and light microscopy for detailed characterization of the behavior of in situ forming PLGA implants in the hydrogel matrix mimicking the subcutis. The model compounds, piroxicam and α-lactalbumin were added to PLGA-1-methyl-2-pyrrolidinone and PLGA-triacetin solutions. Upon bringing the PLGA-solvent-compound pre-formulation in contact with the hydrogel, Vis imaging and light microscopy were applied to visualize the depot formation and UV imaging was used to quantify drug transport in the hydrogel. As compared to piroxicam, the α-lactalbumin invoked an acceleration of phase separation and an increase of implant size. α-Lactalbumin was released faster from the PLGA-1-methyl-2-pyrrolidinone system than the PLGA-triacetin system opposite to the piroxicam release pattern. A linear relationship between the rate of implant formation and initial compound release within the first 4h was established for the PLGA-NMP systems. This implies that phase separation may be one of the controlling factors in drug release. The rate of implant formation may be an important parameter for predicting and tailoring drug release. The approach combining UV imaging, Vis imaging and light microscopy may facilitate understanding of release processes and holds potential for becoming a useful tool in formulation development of in situ forming implants.

In vivo controlled release of fenretinide from long-acting release depots for chemoprevention of oral squamous cell carcinoma recurrence

Local, long-acting release fenretinide (4HPR) millicylindrical implants were prepared and evaluated for their release kinetics in vivo and their ability to suppress oral cancer tumor explant growth. Poly(lactic-co-glycolic acid)(PLGA) implants were prepared as a function of drug loading and the presence of various excipients (pore-formers, solubilizers, crystallization inhibitors) to enhance release of the insoluble 4HPR. Release kinetics and bioerosion of PLGA were monitored both in vitro in a PBS/Tween 80 buffer and in vivo by recovery of the drug remaining at the injection site. 4HPR was released from PLGA implants much slower in vivo than in the drug solubilizing media in vitro, with a 3-week lag phase and continuous release of >2 months, but showed some release enhancement by addition of solubilizers. Water-soluble PVA/sucrose implants for release of 4HPR served to determine if drug dissolution provided suitable controlled release without the PLGA, and this formulation showed continuous drug release over 6 weeks in vivo. Placement of PLGA-4HPR implants adjacent to oral cancer tumor murine xenografts showed inhibition of tumor growth relative to sham implants, indicating the potential for the local 4HPR delivery approach to be useful for oral cancer chemoprevention.