Evaluation of thermal- and photo-crosslinked biodegradable poly(propylene fumarate)-based networks

Biodegradable networks of poly(propylene fumarate) (PPF) and the crosslinking reagent poly(propylene fumarate)-diacrylate (PPF-DA) were prepared with thermal- and photo-initiator systems. Thermal-crosslinking was performed with benzoyl peroxide (BP), which is accelerated by N,N-dimethyl-p-toluidine (DMT) and enables injection and in situ polymerization. Photo-crosslinking was accomplished with bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO), which is activated by long-wavelength UV light and facilitates material processing with rapid manufacturing techniques, such as stereolithography. Networks were evaluated to assess the effects of the initiators and the PPF/PPF-DA double bond ratio on the mechanical properties. Regardless of the initiator system, the compressive properties of the PPF/PPF-DA networks increased as the double bond ratio decreased from 2 to 0.5. BAPO/UV-initiated networks were significantly stronger than those formed with BP/DMT. The compressive modulus of the photo- and thermal-crosslinked PPF/PPF-DA networks ranged from 310 +/- 25 to 1270 +/- 286 MPa and 75 +/- 8 to 332 +/- 89 MPa, respectively. The corresponding fracture strengths varied from 58 +/- 7 to 129 +/- 17 MPa and 31 +/- 13 to 105 +/- 12 MPa. The mechanical properties were not affected by the initiator concentration. Characterization of the network structures indicated that BAPO was a more efficient initiator for the crosslinking of PPF/PPF-DA, achieving a higher double bond conversion and crosslinking density than its BP counterpart. Estimated average molecular weights between crosslinks (Mc) confirmed the effects of the initiators and PPF/PPF-DA double bond ratio on the mechanical properties. This work demonstrates the capability to control the properties of PPF/PPF-DA networks as well as their versatility to be used as an injectable material or a prefabricated implant.     

Injectable biodegradable polymer composites based on poly(propylene fumarate) crosslinked with poly(ethylene glycol)-dimethacrylate

New injectable, in situ crosslinkable biodegradable polymer composites were investigated consisting of poly(propylene fumarate) (PPF), poly(ethylene glycol)-dimethacrylate (PEG-DMA), and beta-tricalcium phosphate (beta-TCP). We examined the effects of the PEG-DMA/PPF double-bond ratio and beta-TCP content on the crosslinking characteristics of the composites including the maximum crosslinking temperature and the gel point, as well as the properties of the crosslinked composites such as the compressive strength and modulus, and the water-holding capacity. The maximum crosslinking temperature was constant averaging 39.7 degrees C for the composite formulations tested. The gel points varied from 8.0 +/- 1.0 to 12.6 +/- 2.5 min and were not affected by the relative amounts of PEG-DMA. The compressive strength at yield of PEG-DMA/PPF composites without beta-TCP increased from 5.9 +/- 1.0 to 11.2 +/- 2.2 MPa as the double-bond ratio of PEG-DMA/PPF increased from 0.38 to 1.88. An increase in compressive modulus was also observed from 30.2 +/- 3.5 to 58.4 +/- 6.2 MPa for the same range of the PEG-DMA/PPF double-bond ratio. Also, the addition of beta-TCP (33 wt%) enhanced the mechanical properties of all composites. The equilibrium water content of networks without beta-TCP increased from 21.7 +/- 0.2 to 30.6 +/- 0.2% for a double-bond ratio of PEG-DMA/PPF ranging from 0.38 to 1.88. However, the mechanical properties of the swollen composites under compression were smaller than the dry ones. These data demonstrate the feasibility of fabricating injectable biodegradable polymer composites with engineered mechanical properties for orthopedic tissue engineering.     

Fabrication of poly(propylene fumarate)-based orthopaedic implants by photo-crosslinking through transparent silicone molds

This work presents a new molding process for photo-crosslinked, degradable polymeric networks of poly(propylene fumarate) (PPF) and the crosslinking agent poly(propylene fumarate)-diacrylate (PPF-DA). Transparent room temperature vulcanizing silicone molds were fabricated for parts ranging from simple test coupons to orthopaedic implants. The PPF/PPF-DA resin blend was injected into the cavity and photo-crosslinked as light was transmitted through the mold wall. The volumetric shrinkage, mechanical properties, and the effects of gamma sterilization were reported for molded PPF/PPF-DA networks prepared with varying compositions of the two polymer components. The shrinkage decreased while the mechanical properties displayed a general increasing trend when more of the crosslinking agent was incorporated into the network. Gamma irradiation resulted in an improvement of the mechanical properties. In addition, PPF/PPF-DA replicates of a 70:30 poly(L/DL-lactide) biodegradable fixation plate and a bone allograft interbody fusion spacer were produced to evaluate the performance of PPF/PPF-DA as an orthopaedic implant and allow for a comparison to be made with materials that have been established for clinical use.     

In vitro degradation of polymeric networks of poly(propylene fumarate) and the crosslinking macromer poly(propylene fumarate)-diacrylate

Polymeric networks of poly(propylene fumarate) (PPF) crosslinked with poly(propylene fumarate)-diacrylate (PPF-DA) are currently being investigated as an injectable, biodegradable bone cement. This study examined the effect of crosslinking density, medium pH, and the incorporation of a beta-tricalcium phosphate (beta-TCP) filler on the in vitro degradation of PPF/PPF-DA. Cylindrical specimens were submerged in buffered saline at 37 degrees C and the change in weight, geometry, and compressive mechanical properties were monitored over a 52-week period. All formulations showed an initial increase in modulus and yield strength over the first 12 weeks, achieving maxima of 1307+/-101 and 51+/-3MPa, respectively, for the beta-TCP composite. PPF/PPF-DA networks with the lower crosslinking density demonstrated the greatest degradation with a 17% mass loss. Samples in the lower buffer pH 5.0 compared to physiological pH 7.4 did not show any differences in mass loss, but exhibited a faster decrease in the compressive strength over time. The beta-TCP composites maintained their mechanical properties at the level following their initial increase. These results show that the degradation of PPF/PPF-DA networks can be controlled by the crosslinking density, accelerated at a lower pH, and prolonged with the incorporation of the beta-TCP filler.     

In-situ preparation of poly(propylene fumarate)--hydroxyapatite composite

In-situ precipitation of hydroxyapatite (HAp) in the presence of poly(propylene fumarate) (PPF) is investigated. Amorphous calcium phosphate (ACP) precipitates in the presence of the polymer and remains in the amorphous form for a relatively long time, e.g. even after 24 h of coexistence with the mother solution. Our observations suggest that PPF interacts with the surface of the ACP particles and prevents them from transformation to crystalline hydroxyapatite. The PPF polymer seems to be more efficient in hindering the ACP to HAp transformation at higher pH conditions. From spectroscopic observations we hypothesize that the C=O bond of the PPF molecules interact with the calcium ion of the ACP particles. In case of low molecular weight PPF this interaction may lead to the incorporation of the polymer within the growing ACP particles.     

Degradation and biocompatibility of a poly(propylene fumarate)-based/alumoxane nanocomposite for bone tissue engineering

In this work, we evaluated the in vitro cytotoxicity and in vivo biocompatibility of a novel poly(propylene fumarate) (PPF)-based/alumoxane nanocomposite for bone tissue engineering applications. The incorporation of functionalized alumoxane nanoparticles into the PPF-based polymer was previously shown to significantly increase the material's flexural mechanical properties. In the current study, samples underwent accelerated in vitro degradation to allow the study of biological responses to these materials over the course of their degradation on a shortened timescale. The polymer, a macrocomposite composed of the polymer and micron-sized particles, and the nanocomposite were evaluated at three stages of degradation for in vitro cytotoxicity with a fibroblast cell line and in vivo soft-tissue response after 3 and 12 weeks of implantation in adult goats. All three material groups experienced mass loss during degradation, but the nanocomposite group eroded significantly faster than the other groups. Nondegraded materials demonstrated minimal cytotoxicity and a minor inflammatory response in soft tissue. On the contrary, predegraded samples elicited more pronounced responses, though these were due to the increase in surface area, surface roughness, and fragmentation associated with the degradation process. The presence of alumoxane nanoparticles in the PPF-based nanocomposite did not significantly affect its cytotoxicity or biocompatibility.     

Synthesis and properties of photocross-linked poly(propylene fumarate) scaffolds

The photocross-linking of poly(propylene fumarate) (PPF) to form porous scaffolds for bone tissue engineering applications was investigated. PPF was cross-linked using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and exposure to 30 min of long wavelength ultraviolet (UV) light. The porous photocross-linked PPF scaffolds (6.5 mm diameter cylinders) were synthesized by including a NaCl porogen (70, 80, and 90 wt% at cross-linking) prior to photocross-linking. After UV exposure, the samples were placed in water to remove the soluble porogen, revealing the porous PPF scaffold. As porogen leaching has not been used often with cross-linked polymers, and even more rarely with photoinitiated cross-linking, a study of the efficacy of this strategy and the properties of the resulting material was required. Results show that the inclusion of a porogen does not significantly alter the photoinitiation process and the resulting scaffolds are homogeneously cross-linked throughout their diameter. It was also shown that porosity can be generally controlled by porogen content and that scaffolds synthesized with at least 80 wt% porogen possess an interconnected pore structure. Compressive mechanical testing showed scaffold strength to decrease with increasing porogen content. The strongest scaffolds with interconnected pores had an elastic modulus of 2.3+/-0.5 MPa and compressive strength at 1% yield of 0.11+/-0.02 MPa. This work has shown that a photocross-linking/porogen leaching technique is a viable method to form porous scaffolds from photoinitiated materials.     

Synthesis and properties of photocross-linked poly(propylene fumarate) scaffolds

The photocross-linking of poly(propylene fumarate) (PPF) to form porous scaffolds for bone tissue engineering applications was investigated. PPF was cross-linked using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and exposure to 30 min of long wavelength ultraviolet (UV) light. The porous photocross-linked PPF scaffolds (6.5 mm diameter cylinders) were synthesized by including a NaCl porogen (70, 80, and 90 wt% at cross-linking) prior to photocross-linking. After UV exposure, the samples were placed in water to remove the soluble porogen, revealing the porous PPF scaffold. As porogen leaching has not been used often with cross-linked polymers, and even more rarely with photoinitiated cross-linking, a study of the efficacy of this strategy and the properties of the resulting material was required. Results show that the inclusion of a porogen does not significantly alter the photoinitiation process and the resulting scaffolds are homogeneously cross-linked throughout their diameter. It was also shown that porosity can be generally controlled by porogen content and that scaffolds synthesized with at least 80 wt% porogen possess an interconnected pore structure. Compressive mechanical testing showed scaffold strength to decrease with increasing porogen content. The strongest scaffolds with interconnected pores had an elastic modulus of 2.3 ± 0.5 MPa and compressive strength at 1% yield of 0.11 ± 0.02 MPa. This work has shown that a photocross-linking/porogen leaching technique is a viable method to form porous scaffolds from photoinitiated materials.     

聚丙烯延胡索酸酯的合成、交联及生物力学、体外降解检测

目的 合成新型可注射性生物降解材料聚丙烯延胡索酸酯[poly(propylene fumarate), PPF],检测其交联温度、交联时间、生物力学性能和体外降解过程。方法 合成PPF,将PPF和N-乙烯基吡咯烷酮(N-vinyl pyrrolidinone,N-VP)在过氧化苯甲酰(benzoyl peroxide,BP)催化下交联,并且加入β-磷酸三钙(β-TCP)和氯化钠(NaCl),检测交联温度、时间、生物力学性能,和PMMA骨水泥进行比较。将PPF交联后浸泡于PBS。检测体外降解时质量和力学强度的变化。结果 交联温度在41.2±2.2℃和47.5±1.7℃间,交联时间从8.1±0.8min到63.7±4.4min,PPF的压应力为2.6±0.5MPa到12.0±2.3Mpa,压缩模量为26.6±8.7MPa到252.8±57.6Mpa,体外降解后4周PPF压应力为8.4±1.6Mpa。结论 PPF有合适的交联温度、交联时间和生物力学强度,体外降解过程中力学强度可以维持4周以上,是一个有应用前景的新型可注射生物高分子聚合材料。     

Characterization of porous injectable poly-(propylene fumarate)-based bone graft substitute

The use of bone grafts for orthopedic applications have increased steadily over the past decade. With improvements in surgical technique, combined with an increasing aged population requiring orthopedic treatment, the need for bone grafts substitutes have also increased. To be useful clinically, the bone graft substitute must be biocompatible, bioabsorbable, and have convenient handling properties. In addition, it must possess a microarchitecture that allows cellular ingrowth and remodeling while simultaneously providing mechanical strength. Poly(propylene fumarate) (PPF) has been investigated as an injectable, biodegradable scaffold for orthopedic applications. Various methods to create a porous, interconnected polymer scaffold are available. The foaming technique is a convenient method to accomplish this task. Reactions between bicarbonate salts and weak acids generate CO(2) gas, causing a bubbling reaction during the polymerization process. This technique allows the porosity of the scaffold to be modulated. Image analysis and mechanical testing of porous PPF fabricated using the foaming technique shows that a highly porous, interconnected scaffold can be produced. At approximately 50% porosity, the scaffold has excellent handling properties, contains pore sizes ranging from 50 to 500 mum with an elastic modulus ranging from 20 to 40 MPa. The foaming technique provides an additional method by which clinically useful polymers can be fabricated for use in various bone tissue engineering applications.     

Photocrosslinking characteristics and mechanical properties of diethyl fumarate/poly(propylene fumarate) biomaterials

The development of tissue engineered materials for the treatment of large bone defects would provide attractive alternatives to the autografts, allografts, non-degradable polymers, ceramics, and metals that are currently used in clinical settings. To this end, poly(propylene fumarate) (PPF), a viscous polyester synthesized from diethyl fumarate (DEF), has been studied for use as an engineered bone graft. We have investigated the photocrosslinking of PPF dissolved in its precursor, DEF, using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and low levels of ultraviolet light exposure. A three factor, 2 x 2 x 4 factorial design was developed, studying the effects of PPF number average molecular weight, BAPO initiator content, and DEF content upon photocrosslinking characteristics and mechanical properties. Uncured DEF/PPF solution viscosity fell over three orders of magnitude as DEF content was increased from 0% to 75%. The exothermic photocrosslinking reaction released low levels of heat, with no more than 160J/g released from any formulation tested. As a result, the maximum photocrosslinking temperature remained below 47 degrees C for all samples. Both sol fraction and swelling degree generally increased with increasing DEF content. Compressive mechanical properties were within the range of trabecular bone, with the strongest samples possessing an elastic modulus of 195.3 +/- 17.5 MPa and a fracture strength of 68.8 +/- 9.4MPa. Finally, the results indicate that PPF crosslinking was facilitated at low DEF precursor concentrations, but hindered at higher precursor concentrations. These novel DEF/PPF solutions may be preferred over pure PPF as the basis for an engineered bone graft because they (1) exhibit reduced viscosity and thus are easily handled, (2) form polymer networks with compressive strength at fracture suitable for consideration for trabecular bone replacement, and (3) may be readily fabricated into solids with a wide range of structures.     

Effect of physiological temperature on the mechanical properties and network structure of biodegradable poly(propylene fumarate)-based networks

Poly(propylene fumarate) (PPF)-based networks have exhibited increases in mechanical properties during their initial stages of degradation. This study was designed to investigate whether physiological temperatures are the source of this reinforcing behavior by influencing the formation of additional crosslinks within the network. Utilizing a model PPF network formed with the crosslinking agent poly(propylene fumarate)-diacrylate (PPF-DA), cylindrical specimens were stored in an inert environment and conditioned at -20 and 37 degrees C while their mechanical properties and network structure were monitored over a six week period. The PPF/PPF-DA specimens exposed to physiological temperatures showed an increase in compressive modulus from 1674 +/- 88 to 2059 +/- 75 MPa. The double bond conversion improved as well, from 64 +/- 1 to 70 +/- 1%, indicating that crosslinks were being formed in the network. The additional reactivity occurred exclusively with unreacted fumarate bonds. PPF/PPF-DA networks stored at -20 degrees C showed no changes in mechanical properties; however, they increased when subsequently conditioned at 37 degrees C. The results were used to explain that PPF-based networks undergo a biphasic degradation behavior due to the competing hydrolytic degradation and thermal induced crosslinking. In addition, heat treating the networks at higher temperatures can be utilized as a means to further reinforce PPF-based materials.     

Effect of physiological temperature on the mechanical properties and network structure of biodegradable poly(propylene fumarate)-based networks

Poly(propylene fumarate) (PPF)-based networks have exhibited increases in mechanical properties during their initial stages of degradation. This study was designed to investigate whether physiological temperatures are the source of this reinforcing behavior by influencing the formation of additional crosslinks within the network. Utilizing a model PPF network formed with the crosslinking agent poly(propylene fumarate)-diacrylate (PPF-DA), cylindrical specimens were stored in an inert environment and conditioned at -20 and 37°C while their mechanical properties and network structure were monitored over a six week period. The PPF/PPF-DA specimens exposed to physiological temperatures showed an increase in compressive modulus from 1674 ± 88 to 2059 ± 75 MPa. The double bond conversion improved as well, from 64 ± 1 to 70 ± 1%, indicating that crosslinks were being formed in the network. The additional reactivity occurred exclusively with unreacted fumarate bonds. PPF/PPF-DA networks stored at -20°C showed no changes in mechanical properties; however, they increased when subsequently conditioned at 37°C. The results were used to explain that PPF-based networks undergo a biphasic degradation behavior due to the competing hydrolytic degradation and thermal induced crosslinking. In addition, heat treating the networks at higher temperatures can be utilized as a means to further reinforce PPF-based materials.     

Characterization of partially saturated poly(propylene fumarate) for orthopaedic application

A partially saturated linear polyester based on poly(propylene fumarate) (PPF) was synthesized for potential application in filling skeletal defects. The synthesis was carried out according to a two-step reaction scheme. Propylene glycol and fumaryl chloride were first combined to form an intermediate fumaric diester. The intermediate was then subjected to a transesterification to form the PPF-based polymer. This method allowed for production of a polymer with a number average molecular weight up to 1500 and a polydispersity index of 2.8 and below. The polymeric backbone structure was investigated through the use of FTIR and NMR. Kinetic studies of the transesterification allowed mapping of the molecular weight increase with reaction time. The final product was also characterized by thermal and solubility analysis.     

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.     

In vivo degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds

This study investigated the in vivo degradation of poly(propylene fumarate) (PPF)/poly(DL-lactic-co-glycolic acid) (PLGA) composite scaffolds designed for controlled release of osteogenic factors. PPF/PLGA composites were implanted into 15.0mm segmental defects in the rabbit radius, harvested after 12 and 18 weeks, and analyzed using histological techniques to assess the extent of polymer degradation as well as the tissue response within the pores of the scaffolds. Polymer degradation was limited to micro-fragmentation of the scaffold at the ends and edges of the implant at both 12 and 18 weeks. The tissue within the pores of the scaffold consisted of fibrous tissue, blood vessels and some inflammatory cells. In areas where polymer breakdown was evident, an increased inflammatory response was observed. In contrast, areas of bone ingrowth into the polymer scaffold were characterized by minimal inflammatory response and polymer degradation. Our results show that minimal degradation of porous PPF occurs within 18 weeks of implantation in a rabbit model. Further, the in vivo degradation data of porous PPF/PLGA scaffolds are comparable with earlier obtained in vitro data.     

In vitro degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds

This study investigated the in vitro degradation of porous poly(propylene fumarate) (PPF-based) composites incorporating microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) during a 26-week period in pH 7.4 phosphate-buffered saline at 37 degrees C. Using a fractional factorial design, four formulations of composite scaffolds were fabricated with varying PEG content of the microparticles, microparticle mass fraction of the composite material, and initial leachable porogen content of the scaffold formulations. PPF scaffolds without microparticles were fabricated with varying leachable porogen content for use as controls. The effects of including PLGA/PEG microparticles in PPF scaffolds and the influence of alterations in the composite formulation on scaffold mass, geometry, water absorption, mechanical properties and porosity were examined for cylindrical specimens with lengths of 13 mm and diameters of 6.5 mm. The composite scaffold composition affected the extent of loss of polymer mass, scaffold length, and diameter, with the greatest loss of polymer mass equal to 15+/-5% over 26 weeks. No formulation, however, exhibited any variation in compressive modulus or peak compressive strength over time. Additionally, sample porosity, as determined by both mercury porosimetry and micro-computed tomography did not change during the period of this study. These results demonstrate that microparticle carriers can be incorporated into PPF scaffolds for localized delivery of bioactive molecules without altering scaffold mechanical or structural properties up to 26 weeks in vitro.     

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.     

Development of biodegradable poly(propylene fumarate)/poly(lactic-co-glycolic acid) blend microspheres. II. Controlled drug release and microsphere degradation

This article describes the effects of six processing parameters on the release kinetics of a model drug Texas red dextran (TRD) from poly(propylene fumarate)/poly(lactic-co-glycolic acid) (PPF/PLGA) blend microspheres as well as the degradation of these microspheres. The microspheres were fabricated using a double emulsion-solvent extraction technique in which the following six parameters were varied: PPF/PLGA ratio, polymer viscosity, vortex speed during emulsification, amount of internal aqueous phase, use of poly(vinyl alcohol) in the internal aqueous phase, and poly(vinyl alcohol) concentration in the external aqueous phase. We have previously characterized these microspheres in terms of microsphere morphology, size distribution, and TRD entrapment efficiency. In this work, the TRD release profiles in phosphate-buffered saline were determined and all formulations showed an initial burst release in the first 2 days followed by a decreased sustained release over a 38-day period. The initial burst release varied from 5.1 (+/-1.1) to 67.7 (+/-3.4)% of the entrapped TRD, and was affected most by the viscosity of the polymer solution used for microsphere fabrication. The sustained release between day 2 and day 38 ranged from 7.9 (+/-0.8) to 27.2 (+/-3.1)% of the entrapped TRD. During 11 weeks of in vitro degradation, the mass of the microspheres remained relatively constant for the first 3 weeks after which it decreased dramatically, whereas the molecular weight of the polymers decreased immediately upon placement in phosphate-buffered saline. Increasing the PPF content in the PPF/PLGA blend resulted in slower microsphere degradation. Overall, this study provides further understanding of the effects of various processing parameters on the release kinetics from PPF/PLGA blend microspheres thus allowing modulation of drug release to achieve a wide spectrum of release profiles.     

Kinetics of poly(propylene fumarate) synthesis by step polymerization of diethyl fumarate and propylene glycol using zinc chloride as a catalyst

Diethyl fumarate and propylene glycol were reacted in the presence of a zinc chloride catalyst to synthesize poly(propylene fumarate) (PPF) over a period of 12 hours. The kinetics of the transesterification polymerization at 130°C, 150°C, and 200°C were determined by gel permeation chromatography (GPC) analysis. The initial rate of polymerization at each temperature was quantified by calculating the rate of change of the number average molecular weight (Mn). At 200°C, gelation of the PPF occurred after 4 h. GPC analysis of the reaction showed that PPF synthesized at 150°C had a higher final Mn of 4600 (±190) and a higher weight average molecular weight of 10 500 (±760) than at 130°C (n = 3). The chemical structure of the PPF was verified by NMR and FT-IR analysis. This study demonstrated that the maximum Mn of PPF by a transesterification reaction is limited due to gelation of PPF at high temperature.