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Cited by 4,816Advanced Drug Delivery Systemsbiodegradable polymer synthesis and propertiesNanoparticle-Based Drug Delivery

Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier

Open access
Makadia, Hirenkumar K., Siegel, Steven J.·2011·Polymers
DOI 10.3390/polym3031377PMC PMC3347861
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Abstract

In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mechanical properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small molecule drugs, proteins and other macromolecules in commercial use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degradation and drug release.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys poly lactic-co-glycolic acid (PLGA) as a biodegradable controlled drug delivery carrier, covering its properties, copolymer systems, fabrication methods, release behavior, degradation factors, toxicology, and modeling. It concludes that PLGA is versatile and FDA-approved, with degradation and release tunable through composition, molecular weight, crystallinity, device geometry, and drug characteristics.

Key findings

  • PLGA is biocompatible, biodegradable, FDA-approved, and can be processed into nanospheres, microspheres, and millimeter-sized implants; it degrades by ester hydrolysis into lactic and glycolic acids, which are eliminated through normal metabolic routes or the kidney.
  • Degradation rate depends strongly on lactide-to-glycolide ratio: 50:50 PLGA degrades fastest, followed by 65:35, 75:25, and 85:15; higher glycolic acid content increases degradation, while higher molecular weight generally slows it. PLGA copolymers have a glass transition temperature above 37 °C and are glassy at physiological temperature.
  • Drug release is often biphasic, with an initial burst followed by slower diffusion and erosion; release is influenced by drug type and load, matrix surface-area-to-volume ratio, pH, crystallinity, and possibly enzymes, though reports on crystallinity and enzymatic degradation conflict.
  • Fabrication approaches include single and double emulsion, coacervation, spray drying, nanoprecipitation, salting out, solvent casting and compression molding, extrusion, supercritical CO₂ foaming, and multifunctional micro/nanoparticles; PLGA/PEG block copolymers can form thermogels but may reduce encapsulation efficiency.

Methods

  • Narrative review of prior literature; no experimental study, systematic search strategy, or primary data collection is described.
  • Synthesizes published work on PLGA physicochemical properties, pharmacokinetics and biodistribution, copolymer architectures, fabrication techniques, drug release behavior, degradation factors, toxicology, and mathematical modeling.
  • Includes equations for diffusion-controlled release, first-order molecular weight loss, and particle-size distributions such as Weibull or Rosin–Rammler models.

Limitations

  • The paper states that mechanisms of PLGA degradation and release are not clearly understood, that crystallinity effects are conflicting, that the role of enzymes is unresolved, and that in vivo and in vitro degradation rates often do not correlate well.
  • It notes that nanoscale PLGA may have distinct biodistribution and toxicological profiles, and that local tissue reactions at application sites can occur, though generally mild.
  • Evident from the text: as a narrative review, it lacks systematic search criteria, quality appraisal, and quantitative synthesis, so conclusions rest on selected cited studies rather than a formal evidence assessment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/polym3031377

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

6 of 116 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The main advantage of solvent-cast implants over micro/nanospheres is the ability to manage adverse events because implants retain a degree of reversibility not available in depot mechanisms.

    “The main advantage of this approach over micro/nanospheres is related to the ability to manage adverse events, since implants retain a degree of reversibility which is not available in depot mechanisms [12,59].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [12] Siegel, 2006, Effect of drug type on the degradation rate of PLGA matrices, Eur. J. Pharm. Biopharm. source
    • cites [59] Rabin, 2008, In vitro and in vivo demonstration of risperidone implants in mice, Schizophr. Res. source
  • Premisecitation

    The high rate of clearance of micro/nanoparticles by the reticuloendothelial system and difficulty penetrating many tissue types may limit their use to the vascular space.

    “However, the high rate clearance of micro/nanoparticles by the body’s reticuloendothelial system (RES) and the difficultyfor such particles to penetrate many tissue types may limit their use to the vascular space [69–71].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [69] Xu, 2010, Synthesizing and binding dual-mode poly (lactic-co-glycolic acid) (PLGA) nanobubbles for cancer targeting and imaging, Biomaterials source
    • cites [70] Zhang, 2010, Multifunctional microbubbles for image-guided antivascular endothelial growth factor therapy, J. Biomed. Opt. source

      The Abstract discusses micro- and nanobubbles for imaging and intraocular drug delivery, but does not address clearance by the reticuloendothelial system or difficulty penetrating tissue. Searches for those mechanisms and for confinement to the vascular space found no relevant passage in our copy. Page numbers were not provided. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [71] Sun, 2008, Multifunctional poly(D,L-lactide-co-glycolide)/ montmorillonite (PLGA/MMT) nanoparticles decorated by Trastuzumab for targeted chemotherapy of breast cancer, Biomaterials source
  • Premisecitation

    Multifunctional particles can be formulated from a component material to reduce side effects of the encapsulated drug.

    “Such multifunctional particles can also be formulated from a component material to reduce side effects of the encapsulated drug [70].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [70] Zhang, 2010, Multifunctional microbubbles for image-guided antivascular endothelial growth factor therapy, J. Biomed. Opt. source

      The paper describes multifunctional PLGA microbubbles made from a biocompatible, biodegradable material for targeted delivery (Abstract; page unavailable). It does not report reduced drug side effects; the encapsulated substance in this study was Texas Red dye, while the anti-VEGF drug Avastin was conjugated to the microbubble surface. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    PLGA is FDA-approved.

    “PLGA are a family of FDA-approved biodegradable polymers that are physically strong and highly biocompatible and have been extensively studied as delivery vehicles for drugs, proteins and various other macromolecules such as DNA, RNA and peptides [1–3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Bouissou, 2006, The influence of surfactant on PLGA microsphere glass transition and water sorption: Remodeling the surface morphology to attenuate the burst release, Pharm. Res. source
    • cites [2] Jain, 2000, The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices, Biomaterials source
    • cites [3] Ruhe, 2003, rhBMP-2 release from injectable poly (DL-lactic-co-glycolic acid)/calcium-phosphate cement composites, J. Bone Jt. Surg. source
  • Premisecitation

    PLGA is highly biocompatible.

    “PLGA are a family of FDA-approved biodegradable polymers that are physically strong and highly biocompatible and have been extensively studied as delivery vehicles for drugs, proteins and various other macromolecules such as DNA, RNA and peptides [1–3].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Bouissou, 2006, The influence of surfactant on PLGA microsphere glass transition and water sorption: Remodeling the surface morphology to attenuate the burst release, Pharm. Res. source
    • cites [2] Jain, 2000, The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices, Biomaterials source
    • cites [3] Ruhe, 2003, rhBMP-2 release from injectable poly (DL-lactic-co-glycolic acid)/calcium-phosphate cement composites, J. Bone Jt. Surg. source
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 27

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Solvent casting is a method to fabricate macroscopic millimeter-sized formulations that can be implanted or inserted for long-term medication.

    “Solvent casting is a method to fabricate a macroscopic millimeter size formulation which can be implanted or inserted for long term medication [59].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [59] Rabin, 2008, In vitro and in vivo demonstration of risperidone implants in mice, Schizophr. Res. source

      The Materials and Methods (page not given) describe solvent casting risperidone and polymer, then molding or extruding the film into implantable pellets or rods. The Introduction and Conclusions describe long-term drug delivery, but the passages do not specify millimeter-sized dimensions; the demonstrated use is a risperidone implant in mice, not a general formulation for long-term medication. (LLM, conf=0.81)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PLGA/PEG block copolymers have been made as diblock PLGA-PEG or as triblock molecules of ABA (PLGA-PEG-PLGA) and BAB (PEG-PLGA-PEG) types.

    “PLGA/PEG block copolymers have been processed as diblock (PLGA-PEG) [18,19] or triblock molecules with both ABA (PLGA-PEG-PLGA) [20] and BAB (PEG-PLGA-PEG) [21] types.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [18] Cheng, 2007, Formulation of functionalized PLGA-PEG Nanoparticles for in vivo targeted drug delivery, Biomaterials source
    • cites [19] Li, 2001, PEGylated PLGA nanoparticles as protein carriers: Synthesis, preparation and biodistribution in rats, J. Control. Release source
    • cites [20] Ghahremankhani, 2007, PLGA-PEG-PLGA tri-block copolymers as an in-situ gel forming system for calcitonin delivery, Polym. Bull. source
    • cites [21] Jeong, 2000, In situ gelation of PEGPLGAPEG triblock copolymer aqueous solutions and degradation thereof, J. Biomed. Mater. Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Extrusion is a continuous process that draws a polymer-drug mixture through a die to create implants of fixed cross-sectional profile without solvent.

    “Unlike solvent-casting, extrusion is a continuous process of drawing polymer-drug mixture through a die to create implants of fixed cross-sectional profile without any use of solvent.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [61] Wang, 2010, A rapid method for creating drug implants: Translating laboratory-based methods into a scalable manufacturing process, J. Biomed. Mater. Res. Part B Appl. Biomater. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many studies have examined PLGA as a carrier for small molecules, proteins, DNA, RNA, and peptides.

    “PLGA are a family of FDA-approved biodegradable polymers that are physically strong and highly biocompatible and have been extensively studied as delivery vehicles for drugs, proteins and various other macromolecules such as DNA, RNA and peptides [1–3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Bouissou, 2006, The influence of surfactant on PLGA microsphere glass transition and water sorption: Remodeling the surface morphology to attenuate the burst release, Pharm. Res. source
    • cites [2] Jain, 2000, The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices, Biomaterials source
    • cites [3] Ruhe, 2003, rhBMP-2 release from injectable poly (DL-lactic-co-glycolic acid)/calcium-phosphate cement composites, J. Bone Jt. Surg. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PLGA is physically strong.

    “PLGA are a family of FDA-approved biodegradable polymers that are physically strong and highly biocompatible and have been extensively studied as delivery vehicles for drugs, proteins and various other macromolecules such as DNA, RNA and peptides [1–3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Bouissou, 2006, The influence of surfactant on PLGA microsphere glass transition and water sorption: Remodeling the surface morphology to attenuate the burst release, Pharm. Res. source
    • cites [2] Jain, 2000, The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices, Biomaterials source
    • cites [3] Ruhe, 2003, rhBMP-2 release from injectable poly (DL-lactic-co-glycolic acid)/calcium-phosphate cement composites, J. Bone Jt. Surg. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Salting out is a method for nanoparticle formulation in which a water-in-oil emulsion containing polymer, solvent, salt, and stabilizer is formed, then water is added to diffuse acetone into water.

    “Salting out is another method in which a water-in-oil emulsion is first formed containing polymer, solvent (usually non chlorinated like acetone), salt (e.g., magnesium acetate tetrahydrate) and stabilizer. Water is then added to the solution until the volume is sufficient to diffuse acetone into the water, resulting in nanoparticle formulations [55–58].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [55] Lamprecht, 2000, Influences of process parameters on nanoparticle preparation performed by a double emulsion pressure homogenization technique, Int. J. Pharm. source
    • cites [56] Murakami, 1999, Preparation of poly(D,L-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method, Int. J. Pharm. source
    • cites [57] Konan, 2003, Preparation and characterization of sterile sub-200 nm meso-tetra(4-hydroxylphenyl)porphyrin-loaded nanoparticles for photodynamic therapy, Eur. J. Pharm. Biopharm. source
    • cites [58] Kwon, 2001, Preparation of PLGA nanoparticles containing estrogen by emulsification-diffusion method, Colloids Surf. A Physicochem. Eng. Asp. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The main disadvantage of spray drying is adhesion of microparticles to the spray-dryer's inner walls.

    “The main disadvantage of this process is the adhesion of the microparticles to the inner walls of the spray-dryer.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A modified double or multiple emulsion technique has become the preferred protocol for encapsulating hydrophilic compounds and proteins.

    “A modification on this procedure called the double or multiple emulsion technique has become the favored protocol for encapsulating hydrophilic compounds and proteins [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Mao, 2007, Effect of WOW process parameters on morphology and burst release of FITC-dextran loaded PLGA microspheres, Int. J. Pharm. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PLGA dissolves in many common solvents, including chlorinated solvents, tetrahydrofuran, acetone, and ethyl acetate.

    “It is soluble in wide range of common solvents including chlorinated solvents, tetrahydofuran, acetone or ethyl acetate [7,10].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Uhrich, 1999, Polymeric systems for controlled drug release, Chem. Rev. source
    • cites [10] Wu, 2001, Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers. Part II: Biodegradation, J. Biomater. Sci. Polym. Ed. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microfluidic devices can use electrostatic forces to control particle size and shape, which allows better tuning of release characteristics.

    “Additionally, microfluidic devices can incorporate the use of electrostatic forces to control the size and shape of particles for increased tuning of release characteristics [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Loscertales, 2002, Micro/Nano encapsulation via electrified coaxial liquid jets, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nanoparticles can be synthesized by nanoprecipitation, in which polymer and drug are dissolved in acetone and added to an aqueous solution containing Pluronic F68, then acetone is evaporated to leave drug-encapsulated nanoparticles.

    “Nanoparticles can also be synthesized by nanoprecipitation methods. Polymer and drug are dissolved in acetone and added to an aqueous solution containing Pluronic F68. The acetone is evaporated at appropriate temperatures and reduced pressures leaving behind the polymer encapsulated nanoparticles with drug [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Hans, 2002, Biodegradable nanoparticles for drug delivery and targeting, Curr. Opin. Solid State Mater. Sci. source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Peptide and protein drugs may need parenteral formulations to avoid digestive-tract degradation and first-pass metabolism, and their short circulating half-lives create a need for parenteral formulations that reduce dosing frequency.

    “Drug delivery of peptides and proteins may also require parenteral formulations to avoid degradation in the digestive tract and first pass metabolism, while the short circulating half-lives of peptides and proteins contribute to the need for parenteral formulations that will reduce dosing frequency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Methyl side groups in PLA make it more hydrophobic than PGA; therefore, lactide-rich PLGA copolymers are less hydrophilic, take up less water, and degrade more slowly.

    “Presence of methyl side groups in PLA makes it more hydrophobic than PGA and hence lactide rich PLGA copolymers are less hydrophilic, absorb less water and subsequently degrade more slowly.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Spray drying is rapid, convenient, and has few processing parameters, making it suitable for industrial-scale processing.

    “Alternatively, spray drying is very rapid, convenient and has very few processing parameters, making it suitable for industrial scalable processing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    The copolymer is usually a free-flowing solution at low temperature and forms a high-viscosity gel at body temperature.

    “The copolymer is usually a free flowing solution at low temperature and can form a high viscosity gel at body temperature.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The mechanical strength, swelling behavior, hydrolysis capacity, and biodegradation rate of PLGA are directly affected by its crystallinity, which in turn depends on the type and molar ratio of monomers in the copolymer.

    “Mechanical strength, swelling behavior, capacity to undergo hydrolysis and subsequently biodegradation rate of the polymer are directly influenced by the degree of crystallinity of the PLGA, which is further dependent on the type and molar ratio of the individual monomer components in the copolymer chain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Emulsion techniques need precise control of processing parameters for high encapsulation efficiency, while phase separation tends to produce agglomerated particles and requires removing large amounts of organic phase, making mass production difficult.

    “Emulsion techniques require precise control of processing parameters for higher encapsulation efficiency, and phase separation techniques tend to produce agglomerated particles and also require removal of large quantities of the organic phase from the microspheres. This makes the process difficult for mass production.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The crystallinity and melting point of PLGA polymers are directly related to molecular weight.

    “Degree of crystallinity and melting point of the polymers are directly related to the molecular weight of the polymer.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Biocompatibility is not an intrinsic material property; it depends on the biological environment and on tolerability of specific interactions among drug, polymer, and tissue.

    “Biocompatibility is clearly important, although it is important to note that biocompatibility is not an intrinsic property of a material, but depends on the biological environment and the tolerability that exists with respect to specific drug-polymer-tissue interactions [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Anderson, 1997, Biodegradation and biocompatibility of PLA and PLGA microspheres, Adv. Drug Deliv. Rev. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Coaxial capillary flows have become a preferred technique for producing monodispersed micro/nanoparticles with simple or core-shell structure because they precisely control mean particle size.

    “Recently, coaxial capillary flows have become a preferable technique to produce monodispersed micro/nanoparticles with either simple or core-shell structure because of their precise control on mean particle size [50,51].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Barrero, 2007, Micro- and nanoparticles via capillary flows, Annu. Rev. Fluid Mech. source
    • cites [51] Freitas, 2005, Microencapsulation by solvent extraction/evaporation: Reviewing the state of the art of microsphere preparation process technology, J. Control. Release source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Drugs in such polymeric devices are released by diffusion through the polymer barrier, by erosion of the polymer, or by both mechanisms.

    “Drugs formulated in such polymeric devices are released either by diffusion through the polymer barrier, or by erosion of the polymer material, or by a combination of both diffusion and erosion mechanisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Higher PGA content generally accelerates degradation, except at a 50:50 PLA/PGA ratio, which degrades fastest; below 50% PGA, increasing PGA content lengthens the degradation interval.

    “As a rule, higher content of PGA leads to quicker rates of degradation with an exception of 50:50 ratio of PLA/PGA, which exhibits the fastest degradation, with higher PGA content leading to increased degradation interval below 50%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PLGA carriers degrade quickly at first (about 30%) and then more slowly, eventually being cleared by respiration in the lung.

    “The degradation of the PLGA carriers is quick on the initial stage (around 30%) and slows eventually to be cleared by respiration in the lung [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Bazile, 1992, Body distribution of fully biodegradable [14C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats, Biomaterials source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Spray drying is known to encapsulate all kinds of drugs, peptides, and proteins into microparticles without significant loss of biological activity.

    “This method is known to encapsulate all kinds of drugs/peptides/proteins into microparticles without significant loss in their biological activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Crystalline PGA copolymerized with PLA lowers PLGA crystallinity and thereby raises the rate of hydration and hydrolysis.

    “Crystalline PGA, when co-polymerized with PLA, reduces the degree of crystallinity of PLGA and as a result increase the rate of hydration and hydrolysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    ABA and BAB triblock copolymers can act as thermogels, with the A block covalently linked to the B block through an ester bond.

    “Triblock copolymers of both ABA and BAB type can act as a thermogel with an A-block covalently coupled with a B-block via ester link.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The glass transition temperature of PLGA copolymers is reported to be above 37 °C, so they are glassy and have a fairly rigid chain structure.

    “The Tg (glass transition temperature) of the PLGA copolymers are reported to be above the physiological temperature of 37 °C and hence are glassy in nature, thus exhibiting fairly rigid chain structure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The solvent used, solvent evaporation temperature, and feed rate affect microsphere morphology.

    “The nature of solvent used, temperature of the solvent evaporation and feed rate affects the morphology of the microspheres.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Double emulsion methods are best for water-soluble drugs such as peptides, proteins, and vaccines, whereas single emulsion methods are ideal for water-insoluble drugs such as steroids.

    “Water-in-oil-in-water emulsion methods are best suited to encapsulate water-soluble drugs like peptides, proteins, and vaccines, unlike single emulsion methods which is ideal for water-insoluble drugs like steroids.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The PEG layer acts as a barrier, reducing interactions with foreign molecules through steric and hydrated repulsion, which improves shelf stability.

    “This layer of PEG acts as a barrier and reduces the interactions with foreign molecules by steric and hydrated repulsion, giving enhanced shelf stability [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Tobio, 1998, Stealth PLA-PEG nanoparticles as protein carriers for nasal administration, Pharm. Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The role of enzymes in PLGA biodegradation is unclear, with most literature indicating purely hydrolytic degradation but some investigators suggesting an enzymatic role based on differences between in vitro and in vivo degradation rates.

    “The role of enzymes in any PLGA biodegradation is unclear. Most literature indicate that the PLGA biodegradation does not involve any enzymatic activity and is purely through hydrolysis. However, some investigators have suggested an enzymatic role in PLGA breakdown based upon the difference in the in vitro and in vivo degradation rates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Alexis, 2005, Factors affecting the degradation and drug-release mechanism of poly (lactic acid) and poly [(lactic acid)-co-(glycolic acid)], Polym. Int. source

  • May combine two claims.

    Premisecitation

    Denatured species are therapeutically inactive and can cause unpredictable side effects such as immunogenicity or other toxicity.

    “Denatured species are therapeutically inactive and can cause unpredictable side effects, such as immunogenicity or other toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Widmer, 1998, Manufacture of porous biodegradable polymer conduits by an extrusion process for guided tissue regeneration, Biomaterials source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are conflicting reports on the effect of crystallinity on the degradation rate.

    “At the moment, there are conflicting reports on the effect of crystallinity on the degradation rate [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Alexis, 2005, Factors affecting the degradation and drug-release mechanism of poly (lactic acid) and poly [(lactic acid)-co-(glycolic acid)], Polym. Int. source

  • May combine two claims.

    Premisecitation

    PLGA polymer biodegrades into lactic and glycolic acids, which are metabolized or excreted and eventually eliminated as carbon dioxide and water.

    “The PLGA polymer biodegrades into lactic and glycolic acids. Lactic acid enters the tricarboxylic acid cycle and is metabolized and subsequently eliminated from the body as carbon dioxide and water [75]. Glycolic acid is either excreted unchanged in the kidney or it enters the tricarboxylic acid cycle and is eventually eliminated as carbon dioxide and water.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Crotts, 1998, Protein delivery from poly (lactic-co-glycolic acid) biodegradable microspheres: Release kinetics and stability issues, J. Microencapsul. source

  • May combine two claims.

    Premisecitation

    After pressurization and rapid depressurization with CO2, thermodynamic instability leads to CO2 clustering inside the liquid polymer, and as CO2 leaves, the emulsion results in a porous polymer structure.

    “After such pressurization and rapid depressurization sequence, the thermodynamic instability of CO2 molecules leads to their clustering inside the liquid polymer. As CO2 leaves, the emulsion results in a porous polymer structure [66,67].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] Koushik, 2004, Preparation of large porous Deslorelin-PLGA microparticles with reduced residual solvent and cellular uptake using a supercritical carbon dioxide process, Pharm. Res. source
    • cites [67] Davies, 2008, Applications of supercritical CO2 in the fabrication of polymer systems for drug delivery and tissue engineering, Adv. Drug Deliv. Rev. source

  • May combine two claims.

    Premisecitation

    PLGA 50:50 exhibits faster degradation than PLGA 65:35, which is faster than PLGA 75:25, which is faster than PLGA 85:15.

    “PLGA 50:50 (PLA/PGA) exhibited a faster degradation than PLGA 65:35 due to preferential degradation of glycolic acid proportion assigned by higher hydrophilicity. Subsequently PLGA 65:35 shows faster degradation than PLGA 75:25 and PLGA 75:25 than PLGA 85:15 [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Park, 1995, Degradation of poly(lactic-co-glycolic acid) microspheres: Effect of copolymer composition, Biomaterials source

  • May combine two claims.

    Premisecitation

    Solvent-casting and compression molding are not continuous processes, which may increase batch-to-batch variation in implant composition and manufacturing cost.

    “Third, solvent-casting and compression molding are not continuous processes, which may increase batch-to-batch variation in the composition of implants as well as cost of manufacturing [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Widmer, 1998, Manufacture of porous biodegradable polymer conduits by an extrusion process for guided tissue regeneration, Biomaterials source

  • May combine two claims.

    Premisecitation

    The ratio of surface area to volume is a significant factor for degradation of large devices, with higher surface area ratio leading to higher degradation.

    “The ratio of surface area to volume has shown to be a significant factor for degradation of large devices. Higher surface area ratio leads to higher degradation of the matrix.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [82] Schliecker, 2003, Hydrolytic degradation of poly(lactide-co-glycolide) films: Effect of oligomers on degradation rate and crystallinity, Int. J. Pharm. source
    • cites [86] Witt, 2001, Morphological characterization of microspheres, films and implants prepared from poly(lactide-co-glycolide) and ABA triblock copolymers: Is the erosion controlled by degradation, swelling or diffusion?, Eur. J. Pharm. Biopharm. source
    • cites [87] Grizzi, 1995, Hydrolytic degradation of devices based on poly(DL-lactic acid) size-dependence, Biomaterials source

  • May combine two claims.

    Interpretationnone given

    In general, PLGA degradation and drug release rate can be accelerated by greater hydrophilicity, increase in chemical interactions among hydrolytic groups, less crystallinity and larger volume to surface ratio of the device.

    “In general, the PLGA degradation and the drug release rate can be accelerated by greater hydrophilicity, increase in chemical interactions among the hydrolytic groups, less crystallinity and larger volume to surface ratio of the device.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The first stage of drug release is through random scission of the polymer without polymer weight loss and is mainly through diffusion, while the second stage is characterized by the onset of weight loss.

    “The first stage of drug release is through random scission of the polymer without any polymer weight loss and is mainly through diffusion, while the second stage is characterized by the onset of weight loss.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Berchane, 2007, Effect of mean diameter and polydispersity of PLG microspheres on drug release: Experiment and theory, Int. J. Pharm. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several studies suggest that nanoparticles of any material may create specific biodistribution and toxicological profiles.

    “Several studies suggest that nanoparticles of any material may create specific biodistribution and toxicological profiles [95].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Olivier, 1999, Indirect evidence that drug brain targeting using polysorbate 80-coated polybutylcyanoacrylate nanoparticles is related to toxicity, Pharm. Res. source

  • May combine two claims.

    Interpretationreasoning

    Multiple studies demonstrate that PLGA can be formulated into drug carrying devices at all scales, can encapsulate a wide range of drugs, peptides or proteins, and can be delivered over different periods with diverse routes.

    “Furthermore, multiple studies demonstrate that PLGA can easily be formulated into the drug carrying devices at all scales, i.e., as nanospheres, as microspheres and even as millimeter sized implants, can encapsulate a wide range of drugs, peptides or proteins and can be delivered over different periods of time with diverse routes of delivery.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    A pulsated drug release profile is sometimes preferred over continuous drug presence because continuous presence may lead to receptor downregulation or tolerance development.

    “A pulsated drug release profile is sometimes preferred over the continuous presence of the drug, which may lead to downregulation of receptors or the development of tolerance.”

  • The paper relies on this without support.

    Large macroscopic formulations act as a drug reservoir that can be delivered over a longer interval.

    “Large size, macroscopic formulations act as a reservoir for drug that can be delivered over a longer interval.”

  • The paper relies on this without support.

    All microparticle preparation techniques described earlier can be employed for manufacturing PLGA nanoparticles by adjusting processing parameters.

    “All the above described microparticle techniques can be employed for manufacturing PLGA nanoparticles (nanospheres and nanocapsules) by adjusting the processing parameters.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PLGA allows adjustable degradation rates and hydrophilicity by changing the PGA:PLA ratio, where higher PLA concentrations increase hydrophobicity, degradation time, and incorporated drug release.

    “It allows for adjustable degradation rates and hydrophilicity by changing the PGA:PLA ratio, where higher PLA concentrations increase hydrophobicity, degradation time, and consequently incorporated drug release.[ 201 ]”

    From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [201]

    Section 2.1.1 says lactide-rich PLGA is less hydrophilic and degrades more slowly, supporting the claim about hydrophobicity and degradation time. Section 4.2.1 links greater glycolic acid content—not greater PLA content—to faster degradation and drug release. The claimed increase in drug release with higher PLA content is therefore not supported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PCL, PDLLA, and PLGA are examples of polyesters used to solubilize hydrophobic drugs.

    “Examples of polyesters for solubilizing hydrophobic drugs are PCL, PDLLA and PLGA [106–108].”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [106]

  • Material mineralization can be expedited in the presence of immobilized growth factors.

    “and the material mineralization can be expedited in the presence of immobilized growth factors [91–95].”

    From Polydopamine-Assisted Surface Modification for Bone Biosubstitutes (2016) · cites this paper as [91]

    Section 3 discusses PLGA carriers for delivering drugs and proteins, while Section 5 discusses factors that accelerate PLGA degradation and drug release. Neither addresses whether immobilized growth factors expedite material mineralization (searched: immobilized growth factors, mineralization, and related bone-growth terms). (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Upon immobilization of BMP, the property of osteoblast cells responsive to polymeric materials can be remarkably improved.

    “Upon immobilization of BMP, the property of osteoblast cells responsive to polymeric materials can be remarkably improved”

    From Polydopamine-Assisted Surface Modification for Bone Biosubstitutes (2016) · cites this paper as [91]

    The Introduction describes PLGA as a drug-delivery carrier and tissue-engineering scaffold, and Section 5 discusses controlled delivery of proteins. Neither passage addresses whether immobilizing BMP improves osteoblast responses to polymeric materials; searches for BMP, bone morphogenetic protein, and osteoblast found no passage making that claim. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • Drug release from polyester-based systems occurs via bulk degradation of the polymer and drug diffusion and can be modified by altering the hydrophobicity of the monomer, polymer chain length and particle size.

    “Drug release occurs via bulk degradation of the polymer and drug diffusion 12 and can be modified by altering the hydrophobicity of the monomer, polymer chain length and particle size 13 .”

    From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [13]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Opposite device-size trends for degradation

    Major

    The conclusion says a larger volume-to-surface ratio accelerates degradation, while Section 4.2.5 says a higher surface-area-to-volume ratio increases degradation. These ratios move in opposite directions.

  • PDLA and PLLA are described as physically alike and structurally unlike

    Minor

    The paper calls their physicochemical properties nearly the same, then describes PLLA as highly crystalline and PDLA as completely amorphous. Those are substantially different physical properties.

  • Opposite device-size ratios are said to accelerate degradation

    Minor

    The discussion says a higher surface-area-to-volume ratio increases degradation, while the conclusion says a larger volume-to-surface ratio accelerates it. Those ratios move in opposite directions.

  • The model reverses its boundary and initial-condition labels

    Minor

    Equation (3), called an initial condition, instead specifies concentration at the particle surface for times greater than zero. Equation (2), called a boundary condition, is restricted to time zero.

4 of 4

Cites

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Cited by

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Related

Authors
Makadia, H. K., & Siegel, S. J.
Affiliations
University of Pennsylvania (US)
Corresponding author
Siegel, Steven J.
ORCID
Venue
Polymers
Publisher
MDPI AG
Published
2011-08-26
Volume
3
Issue
3
Pages
1377-1397
ISSN
2073-4360 (ISSN-L)
DOI
10.3390/polym3031377
PMC
PMC3347861
OpenAlex
W2087032263
Semantic Scholar
3649c008437b4a4a59c67419af5d7fe7bf3594a7
Cited by
4,816
References
98
Citations by year
2026: 490 · 2025: 477 · 2024: 387 · 2023: 394 · 2022: 419 · 2021: 406 · 2020: 435 · 2019: 412 · 2018: 373 · 2017: 305 · 2016: 266 · 2015: 212 · 2014: 138 · 2013: 75 · 2012: 24
FWCI
46.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Polymers (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Mental Health (R01MH074672)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Physical Sciences › Materials Science › Biomaterials › biodegradable polymer synthesis and properties
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
poly(lactic-co-glycolic acid), PLGA, controlled drug delivery, biodegradable polymers, biocompatibility, drug release, polymer degradation, tissue engineering, small molecule drugs, protein delivery, macromolecule delivery

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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