Development of an injectable two-phase drug delivery system for sequential release of antiresorptive and osteogenic drugs

Unlike controlled release systems that deliver a single drug, dual or multidrug delivery systems with distinct release profiles are more likely to promote timely and effective tissue regeneration as they provide both temporally and concentration-dependent release of different molecules to mimic natural biological events. In this study, an injectable and biodegradable delivery system was developed to sequentially release an antiresorptive drug (clodronate) followed by an osteogenic agent (simvastatin) to treat bone disease. The injectable delivery system comprised simvastatin-loaded gelatin microspheres suspended in a viscous solution of carboxymethylcellulose (CMC) containing clodronate. Several factors (CMC concentration, glutaraldehyde concentration, simvastatin loading, and gelatin microsphere processing conditions) were investigated for their effects on drug release. Clodronate release was not affected by CMC concentration, with complete delivery within 12 hr, and simvastatin release could be modulated by cross-linking of the gelatin microspheres, loading, and washing conditions. Burst release of simvastatin was reduced from 70% to 6% in conjunction with sustained release for up to 3 weeks. The combined system showed early release of the antiresorptive clodronate sequentially followed by sustained delivery of the osteogenic simvastatin. This robust and flexible two-phase delivery system may prove useful for applications in which multiple drug delivery is desired.     

Sustained release of antibiotics from injectable and thermally responsive polypeptide depots

Biodegradable polymeric scaffolds are of interest for delivering antibiotics to local sites of infection in orthopaedic applications, such as bone and diarthrodial joints. The objective of this study was to develop a biodegradable scaffold with ease of drug loading in aqueous solution, while providing for drug depot delivery via syringe injection. Elastin-like polypeptides (ELPs) were used for this application, biopolymers of repeating pentapeptide sequences that were thermally triggered to undergo in situ depot formation at body temperature. ELPs were modified to enable loading with the antibiotics, cefazolin, and vancomycin, followed by induction of the phase transition in vitro. Cefazolin and vancomycin concentrations were monitored, as well as bioactivity of the released antibiotics, to test an ability of the ELP depot to provide for prolonged release of bioactive drugs. Further tests of formulation viscosity were conducted to test suitability as an injectable drug carrier. Results demonstrate sustained release of therapeutic concentrations of bioactive antibiotics by the ELP, with first-order time constants for drug release of approximately 25 h for cefazolin and approximately 500 h for vancomycin. These findings illustrate that an injectable, in situ forming ELP depot can provide for sustained release of antibiotics with an effect that varies across antibiotic formulation. ELPs have important advantages for drug delivery, as they are known to be biocompatible, biodegradable, and elicit no known immune response. These benefits suggest distinct advantages over currently used carriers for antibiotic drug delivery in orthopedic applications.     

壳聚糖微球药物释放机制研究进展

近年来已有多种药物实现了以壳聚糖微球作为缓控释载体,并在生物医学领域展现出良好的应用前景,成为缓控释剂型研究的热点之一。目前对壳聚糖微球释放机制的研究进展落后于壳聚糖载药微球制备与应用的研究进展,而加强壳聚糖载药微球药物释放机制的研究,有利于更好地了解药物的释放行为和释放影响因素,并对深入研究壳聚糖缓释载药体系的制备与应用具有重要意义。主要从壳聚糖微球的药物释放机制、药物释放行为描述、药物释放影响因素等方面进行了综述。     

Controlled drug release from a novel injectable biodegradable microsphere/scaffold composite based on poly(propylene fumarate)

The ideal biomaterial for the repair of bone defects is expected to have good mechanical properties, be fabricated easily into a desired shape, support cell attachment, allow controlled release of bioactive factors to induce bone formation, and biodegrade into nontoxic products to permit natural bone formation and remodeling. The synthetic polymer poly(propylene fumarate) (PPF) holds great promise as such a biomaterial. In previous work we developed poly(DL-lactic-co-glycolic acid) (PLGA) and PPF microspheres for the controlled delivery of bioactive molecules. This study presents an approach to incorporate these microspheres into an injectable, porous PPF scaffold. Model drug Texas red dextran (TRD) was encapsulated into biodegradable PLGA and PPF microspheres at 2 microg/mg microsphere. Five porous composite formulations were fabricated via a gas foaming technique by combining the injectable PPF paste with the PLGA or PPF microspheres at 100 or 250 mg microsphere per composite formulation, or a control aqueous TRD solution (200 microg per composite). All scaffolds had an interconnected pore network with an average porosity of 64.8 +/- 3.6%. The presence of microspheres in the composite scaffolds was confirmed by scanning electron microscopy and confocal microscopy. The composite scaffolds exhibited a sustained release of the model drug for at least 28 days and had minimal burst release during the initial phase of release, as compared to drug release from microspheres alone. The compressive moduli of the scaffolds were between 2.4 and 26.2 MPa after fabrication, and between 14.9 and 62.8 MPa after 28 days in PBS. The scaffolds containing PPF microspheres exhibited a significantly higher initial compressive modulus than those containing PLGA microspheres. Increasing the amount of microspheres in the composites was found to significantly decrease the initial compressive modulus. The novel injectable PPF-based microsphere/scaffold composites developed in this study are promising to serve as vehicles for controlled drug delivery for bone tissue engineering.     

Comparative study of nanohydroxyapatite microspheres for medical applications

This study concerns the preparation, physical, and in vitro characterization of two different types of hydroxyapatite (HA) microspheres, which are intended to be used as drug-delivery systems and bone-regeneration matrices. Hydroxyapatite nanoparticles (HA-1 and HA-2) were prepared using the chemical precipitation synthesis with H(3)PO(4), Ca(OH)(2), and a surfactant, SDS (sodium dodecyl sulfate), as starting reagents. The HA powders were dispersed in a sodium alginate solution, and spherical particles were obtained by droplet extrusion coupled with ionotropic gelation in the presence of Ca(2+). These were subsequently sintered to produce HA-1 and HA-2 microspheres with a uniform size and interconnected microporosity. Both powders and microspheres were characterized using FTIR and X-ray diffraction. Moreover, SEM and mercury intrusion porosimetry were used to analyze the microspheres, and TEM was used to analyze the powders. Results showed that pure HA and mixtures of HA/beta-TCP in the nanometer range and needlelike shape were obtained for HA-1 and HA-2 powders, respectively. Neutral Red, scanning electron microscopy and confocal microscopy were used to evaluate the behavior of osteoblastic-like MG-63 cells cultured on HA microspheres surfaces for 7 days. Results showed that good adhesion and proliferation of osteoblasts on the HA microspheres surface. Cells built bridges between adjacent microspheres, forming microspheres-cells clusters in both types of materials.     

Development of a sustained-release system for perivascular delivery of dipyridamole

Vascular access grafts implanted in dialysis patients are prone to failure in the long-term because of stenosis and occlusion caused by neointimal hyperplasia. Local delivery of antiproliferative drugs may be effective to prevent this consequence while minimizing the systemic side effects they cause. We developed a combination of poly(lactide-co-glycolide) (PLGA) microspheres with ReGel, an injectable copolymer, as a sustained-release system for perivascular delivery of an antiproliferative drug, dipyridamole. Dipyridamole-incorporated PLGA microspheres with various molecular weights (MWs) of PLGA were prepared by oil-in-water emulsion method. Encapsulation efficiency and surface morphology of microspheres were characterized. In vitro release kinetics of dipyridamole from ReGel or from microspheres/ReGel was experimentally determined. Without microspheres, 40% of the dipyridamole was released from ReGel as an initial burst in the first 3 days followed by continuous release in the subsequent 2 weeks. The use of PLGA microspheres decreased the initial burst and extended dipyridamole release from 23 to 35 days with increasing MW of PLGA. The highest MW PLGA showed a lag time of 17 days before consistent drug release occurred. Mixing microspheres and ReGel with two different MW PLGA achieved a continuous release for 35 days with little initial burst. In vivo release of dipyridamole from microspheres/ReGel exhibited a comparable release pattern to that seen in vitro. This injectable platform is a promising technique for sustained perivascular delivery of antiproliferative drugs.     

载药硼酸盐骨水泥的制备及其体外生物活性和抗菌性能的研究

目的以硼酸盐生物活性玻璃和改性壳聚糖液相制备了新型的硼酸盐骨水泥,同时负载骨髓炎治疗药物硫酸庆大霉素,考察其体外抗菌性能,以探讨其治疗骨髓炎的可能性。方法以硼酸盐骨水泥为载体,制备了负载硫酸庆大霉素(GS)的骨水泥。探究负载GS对骨水泥的可注射性能、初凝时间的影响;将负载GS且预固化的硼酸盐骨水泥浸泡于磷酸盐缓冲溶液(PBS)中,考察其体外生物活性、生物降解性和药物释放;利用抑菌圈实验评估了负载GS的硼酸盐骨水泥的体外抗菌性能。结果制备的载药硼酸盐骨水泥能够被完全注射,初凝时间约6 min;在体外的磷酸盐缓冲溶液(PBS)中浸泡时,GS能够持续稳定的释放,药物释放长达26天;负载GS的硼酸盐骨水泥能够很好地抑制金黄色葡萄球菌(S.aureus)和大肠杆菌(E.coli)的生长。结论制备的负载GS的硼酸盐骨水泥具有优异的可注射性,合适的原位自固化时间,长期持续的药物释放和抗菌性能,可以用于骨髓炎治疗的进一步研究。     

Controlled release of gentamicin from calcium phosphate-poly(lactic acid-co-glycolic acid) composite bone cement

Modification of a self setting bone cement with biodegradable microspheres to achieve controlled local release of antibiotics without compromising mechanical properties was investigated. Different biodegradable microsphere batches were prepared from poly(lactic-co-glycolic acid) (PLGA) using a spray-drying technique to encapsulate gentamicin crobefate varying PLGA composition and drug loading. Microsphere properties such as surface morphology, particle size and antibiotic drug release profiles were characterized. Microspheres were mixed with an apatitic calcium phosphate bone cement to generate an antibiotic drug delivery system for treatment of bone defects. All batches of cement/microsphere composites showed an unchanged compressive strength of 60 MPa and no increase in setting time. Antibiotic release increased with increasing drug loading of the microspheres up to 30% (w/w). Drug burst of gentamicin crobefate in the microspheres was abolished in cement/microsphere composites yielding nearly zero order release profiles. Modification of calcium phosphate cements using biodegradable microspheres proved to be an efficient drug delivery system allowing a broad range of 10-30% drug loading with uncompromised mechanical properties.     

MBG/PLGA composite microspheres with prolonged drug release

Mesoporous bioactive glass (MBG) and composite microspheres with MBG particles embedded in biodegradable poly(D,L-lactide-co-glycolide) (PLGA) matrix have been prepared and used to load gentamicin (GS). The in vitro drug release experiments from both MBG and composite microspheres were conducted in distilled water and phosphate buffered saline (PBS) solution at 37 degrees C for more than 30 days. In both water and PBS, GS release from the MBG was very fast with about 60 wt % of the loaded drug released in the first 24 h, and more than 80 wt % released in two days. MBG/PLGA composite microspheres showed an initial release of about 33 wt % in the first day, and 48 wt % in 2 days, and a subsequent sustained release lasting for more than 4 weeks in PBS. MBG/PLGA composite microspheres may be used as an alternative drug release system, especially as a bone void filler for bone repair due to their combined advantages of sustained release of antibiotics and apatite-forming ability.     

Novel mesoporous silica-based antibiotic releasing scaffold for bone repair

Tissue engineering scaffolds with a micro- or nanoporous structure and able to deliver special drugs have already been confirmed to be effective in bone repair. In this paper, we first evaluated the biomineralization properties and drug release properties of a novel mesoporous silica–hydroxyapatite composite material (HMS–HA) which was used as drug vehicle and filler for polymer matrices. Biomineralization can offer a credible prediction of bioactivity for the synthetic bone regeneration materials. We found HMS–HA exhibited good apatite deposition properties after being soaked in simulated body fluid (SBF) for 7 days. Drug delivery from HMS–HA particle was in line with Fick’s law, and the release process lasted 12 h after an initial burst release with 60% drug release. A novel tissue engineering scaffold with the function of controlled drug delivery was developed, which was based on HMS–HA particles, poly(lactide-co-glycolide) (PLGA) and microspheres sintering techniques. Mechanical testing on compression, degradation behavior, pH-compensation effect and drug delivery behavior of PLGA/HMS–HA microspheres sintered scaffolds were analyzed. Cell toxicity and cell proliferation on the scaffolds was also evaluated. The results indicated that the PLGA/HMS–HA scaffolds could effectively compensate the increased pH values caused by the acidic degradation product of PLGA. The compressive strength and modulus of PLGA/HMS–HA scaffolds were remarkably high compared to pure PLGA scaffold. Drug delivery testing of the PLGA/HMS–HA scaffolds indicated that PLGA slowed gentamycin sulfate (GS) release from HMS–HA particles, and the release lasted for nearly one month. Adding HMS–HA to PLGA scaffolds improved cytocompatibility. The scaffolds demonstrated low cytotoxicity, and supported mesenchymal stem cells growth more effectively than pure PLGA scaffolds. To summarize, the data supports the development of PLGA/HMS–HA scaffolds as potential degradable and drug delivery materials for bone replacement.     

Design of a multiple drug delivery system directed at periodontitis

Periodontal disease is highly prevalent, with 90% of the world population affected by either periodontitis or its preceding condition, gingivitis. These conditions are caused by bacterial biofilms on teeth, which stimulate a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The present research sought to demonstrate development of a multiple drug delivery system for stepwise treatment of different stages of periodontal disease. More specifically, multilayered films were fabricated from an association polymer comprising cellulose acetate phthalate and Pluronic F-127 to achieve sequential release of drugs. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. Different erosion times and adjustable sequential release profiles were achieved by modifying the number of layers or by inclusion of a slower-eroding polymer layer. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. The multilayered CAPP delivery system offers a versatile approach for releasing different drugs based on the pathogenesis of periodontitis and other conditions.     

Recent developments of collagen-based materials for medical applications and drug delivery systems

In this review, an attempt was made to summarize some of the recent developments in the application of collagen as a biomaterial and in drug delivery systems. The main applications covered include: collagen for burn/wound cover dressings; osteogenic and bone filling materials; antithrombogenic surfaces; and immobilization of therapeutic enzymes. Recently, collagen used as a carrier for drug delivery has attracted many researchers throughout the world. The use of collagen for various drug delivery systems has also been reviewed in this article. Collagen-based drug delivery systems include: injectable microspheres based on gelatin (degraded form of collagen); implantable collagen-synthetic polymer hydrogels; interpenetrating networks of collagen; and synthetic polymers collagen membranes for ophthalmic delivery. Recent efforts to use collagen-liposomal composites for controlled drug delivery, as well as collagen as controlling membranes for transdermal delivery, were also reviewed. In this review, the main emphasis was on the work done in our laboratory.     

人同种异体骨载异烟肼-壳聚糖缓释微球的制备和体内外释药特性☆

背景：壳聚糖微球具有良好的生物相容性及抗菌活性,被广泛地运用于各种药物缓释系统中。 目的：制备人同种异体骨载异烟肼-壳聚糖微球,并分析其体内释药性能。 方法：用喷雾干燥法制备异烟肼-壳聚糖微球,进行体外45 d的药物释放实验。将单独装载异烟肼的异体骨块(对照组)和装载异烟肼-壳聚糖微球的异体骨块(实验组)分别植入家兔两侧髂骨,采用高效液相色谱法检测药物体内释放情况。 结果与结论：异烟肼-壳聚糖微球外观呈圆形、表面光滑、分散良好;平均粒径(3.33±0.9) μm,载药率(16.25±1.24)%。体外药物释放实验显示无突释现象,24 h释放20%左右,45 d释放76%,释放曲线较平缓,释放稳定;数学模型拟合符合Ritger-Peppas模型。实验组异烟肼浓度在前28 d内缓慢升高,其后缓慢下降,持续56 d以上,浓度38.50~155.75 µg/g;对照组异烟肼浓度在1周左右达高峰,为1982.5 µg/g,21 d后骨块周围药物不能测到。说明异烟肼-壳聚糖缓释微球在体内外均可以缓慢平稳释放异烟肼,且持续时间长。提示人同种异体骨载异烟肼-壳聚糖缓释微球复合体可以作为骨结核病灶清除后的一种置入材料,在提供机械支持的同时进行长时间的局部化疗。     

A surface-eroding antibiotic delivery system based on poly-(trimethylene carbonate)

Biodegradable delivery systems that do not produce acidic compounds during degradation are preferred for local antibiotic delivery in bone infections in order to avoid adverse bone reactions. Poly(trimethylene carbonate) (PTMC) has good biocompatibility, and is such a polymer. The objective of this in vitro study was to explore the suitability of PTMC as an antibiotic releasing polymer for the local treatment of bone infections. Degradation behaviour and corresponding release profiles of gentamicin and vancomycin from slowly degrading PTMC₁₆₈ and faster degrading PTMC₃₃₉ discs were compared in the absence and presence of a lipase solution. Gentamicin release in the absence of lipase was diffusion-controlled, while vancomycin release was limited. Surface erosion of PTMC only occurred in the presence of lipase. Both antibiotics were released in high concentrations from PTMC in the presence of lipase through a combination of surface erosion and diffusion. This illustrates the major advantage of surface-eroding biodegradable polymers, allowing release of larger antibiotic molecules like vancomycin.     

In vitro and in vivo testing of bioabsorbable antibiotic containing bone filler for osteomyelitis treatment

The use of local antibiotics from a biodegradable implant is appealing concept for treatment of chronic osteomyelitis. Our aim was to develop a new drug delivery system based on controlled ciprofloxacin release from poly(D/L-lactide). Cylindrical composite pellets (1.0 x 0.9 mm) were manufactured from bioabsorbable poly(D/L-lactide) matrix and ciprofloxacin (7.4 wt %). In vitro studies were carried out to delineate the release profile of the antibiotic and to verify its antimicrobial activity by means of MIC testing. A long-term study in rabbits was performed to validate the release of ciprofloxacin from the composite in vivo. Therapeutic level of ciprofloxacin (>2 microg/mL) was maintained between 60 and 300 days and the concentration remained below the potentially detrimental level of 20 microg/mL in vitro. The released ciprofloxacin had retained its antimicrobial properties against common pathogens. In an exploratory long-term in vivo study with three rabbits, ciprofloxacin could not be detected from the serum after moderate filling (160 mg) of the tibia (follow-up 168 days), whereas after high dosing (a total dose of 1,000 mg in both tibias) ciprofloxacin was found temporarily at low serum concentrations (14-34 ng/mL) during the follow-up of 300 days. The bone concentrations of ciprofloxacin could be measured in all samples at 168 and 300 days. The tested copolylactide matrix seems to be a promising option in selection of resorbable carriers for sustained release of antibiotics, but the composite needs modifications to promote ciprofloxacin release during the first 60 days of implantation.     

Biodegradable poly (lactic acid) microspheres for drug delivery systems

In connection with aim of maximizing the bio-availability of conventional drugs with minimum side-effects, new drug delivery systems (DDS) continue to attracted much attention. The controlled or sustained release of drugs represents one such approach, and in this regard report upon a study of DDS using biodegradable polymers which include poly (lactic acid) (PLA), poly (glycolic acid), and their copolymers (PLGA). Much attention is being paid to the controlled release of bio-active agents from microcapsules and microspheres made of biodegradable polymers, such as lactic acid homopolymers, as well as copolymers of glycolic acid. (11-21) Microcapsules or microspheres are injectable and able to provide pre-programmed durations of action, offering several advantages over the conventional dosage forms. This article reviews the results of a work program conducted in collaboration with a medical doctor upon DDS using biodegradable microspheres, such as PLA and PLGA.     

Controlled and sustained gene delivery from injectable, porous PLGA scaffolds

Biodegradable poly(lactic-co-glycolic acid) (PLGA) scaffolds are widely used for the delivery of therapeutic molecules such as plasmid DNA (pDNA) and growth factors. However, many of these scaffolds must be implanted, and it would be beneficial to develop PGLA systems that can be injected in a minimally invasive manner. In this study, we present an injectable, porous PLGA scaffold that solidifies in situ for controlled gene delivery. Micro-scale porosity was engineered into the system to facilitate cell migration, proliferation and extracellular matrix elaboration. Relatively rapid release of pDNA was achieved through simple mixing into the polymer solution prior to scaffold solidification, whereas sustained release was achieved by incorporating pDNA-laden PLGA microspheres into the polymer solution. Sustained pDNA release was obtained for over 70 days. When the released pDNA was complexed with PEI and used to transfect HEK293 cells, substantial gene transfection was achieved from all time points, demonstrating that the pDNA was bioactive for the entire time course of the study. These in situ forming porous scaffolds for pDNA delivery are easy to prepare and can be injected without invasive surgery. Importantly, localized delivery of bioactive pDNA can be achieved for short to prolonged time periods, and small changes in the system composition permit facile tailoring of release profiles. In the future, this system may be used to control host cell regenerative responses by, for example, inducing cellular migration into the porous scaffold architecture via release of pDNA encoding for chemokines or pro-angiogenic molecules.     

Injectable in situ dual-crosslinking hyaluronic acid and sodium alginate based hydrogels for drug release

A series of injectable in situ dual-crosslinking hydrogels (HA/ALG) based on oxidized sodium alginate (oxi-ALG) and hyaluronic acid modified with thiol and hydrazide (HA-SH/CDH) were prepared via hydrazone bonds and disulfide bonds. The chemical structures, morphologies, rheological properties, gelling time, swelling ratio, degradation rate and drug release behavior of hydrogels were investigated. HA/ALG hydrogels exhibited tunable gelling time, rheological properties, swelling ratio and degradation rate with varying precursor concentrations. The gelling time of HA/ALG hydrogels ranged from 157?s to 955?s, the values of yield stress of HA2/ALG2, HA3/ALG3 and HA4/ALG4 hydrogels were 1724, 4349 and 5306?Pa, and the degradation percentage of HA2/ALG2, HA3/ALG3 and HA4/ALG4 hydrogels were about 64%, 51% and 42% after incubating 35?days, respectively. Bovine serum albumin (BSA) was used as a model drug to investigate the drug controlled release properties, and the in vitro cumulative release percentage of BSA from HA2/ALG2, HA3/ALG3 and HA4/ALG4 drug-loaded hydrogels were about 79%, 72% and 69% after 20?days. The series of injectable in situ dual-crosslinking HA/ALG hydrogels could be an attractive candidate for drug delivery system, tissue engineering and regenerative medicine.     

载药人工骨给药系统治疗骨髓炎的研究与进展

背景：传统口服抗生素治疗因趋化能力弱、剂量难以控制及全身副反应等作用削弱其广泛的应用。载药人工骨长效、定点、可控地释放药物,弥补了系统抗生素治疗的缺陷。 目的：通过新型局部给药系统材料,制备及药物释放动力学等方面综合和对比分析,指导以后载药人工骨的研发和选择应用。 方法：应用PubMed和Sciencedirect数据库检索2001-01/2011-11关于局部给药系统对骨髓炎及骨缺损治疗相关方面的文献,英文检索词为“drug delivery system, osteomyelitis, bone defect, bone substitute”。排除无关及重复性研究,同一领域则选择权威杂志近期发表文献,保留25篇进一步归纳总结。 结果与结论：骨的重建与修复需要满足3个条件,即要满足骨诱导、骨传导和骨生成,此外合适的骨组织生长环境也必不可少。根据材料特点将人工骨分为生物陶瓷材料,生物材料,高分子材料,复合材料。也可根据材料的吸收性分为可生物降解型和非生物降解型。载药人工骨局部给药系统靶位点释放药物,具有提供骨良好修复环境与骨诱导的特点。载药骨的药物释放量需对载药浓度选择,局部药物释放时间,感染类型确定药物种类的选择,人工骨材料选择,药物与人工骨是否发生化学反应,对骨材料性质的影响等方面进行比较和控制。     

Injectable, in situ forming poly(propylene fumarate)-based ocular drug delivery systems

This study sought to develop an injectable formulation for long-term ocular delivery of fluocinolone acetonide (FA) by dissolving the anti-inflammatory drug and the biodegradable polymer poly(propylene fumarate) (PPF) in the biocompatible, water-miscible, organic solvent N-methyl-2-pyrrolidone (NMP). Upon injection of the solution into an aqueous environment, a FA-loaded PPF matrix is precipitated in situ through the diffusion/extraction of NMP into surrounding aqueous fluids. Fabrication of the matrices and in vitro release studies were performed in phosphate buffered saline at 37 degrees C. Drug loadings up to 5% were achieved. High performance liquid chromatography was employed to determine the released amount of FA. The effects of drug loading, PPF content of the injectable formulation, and additional photo-crosslinking of the matrix surface were investigated. Overall, FA release was sustained in vitro over up to 400 days. After an initial burst release of 22 to 68% of initial FA loading, controlled drug release driven by diffusion and bulk erosion was observed. Drug release rates in a therapeutic range were demonstrated. Release kinetics were found to be dependent on drug loading, formulation PPF content, and extent of surface crosslinking. The results suggest that injectable, in situ formed PPF matrices are promising candidates for the formulation of long-term, controlled delivery devices for intraocular drug delivery.