Biocompatibility, biodegradation and biomedical applications of poly(lactic acid)poly(lactic‑co‑glycolic acid) micro and nanoparticles

Purpose: PLA and PLGA are FDA-approved, biodegradable polymers widely used for micro- and nanoparticle drug delivery, but their clinical performance depends on biocompatibility, degradation behavior, and drug-release control. This review addresses the need to understand PLA/PLGA tissue responses, degradation pathways, release models, and biomedical applications, especially for vaccines, drugs, and nucleic acids.

Hypothesis: This is a review article and does not test a single formal hypothesis. Its central premise is that PLA and PLGA micro/nanoparticles are biocompatible and biodegradable, and that their degradation, drug release, and biological performance can be tuned by polymer composition, molecular weight, crystallinity, particle size, and surface modification to enable safe and effective drug, vaccine, and gene delivery.

Aims: Review the biocompatibility and biodegradation of PLA, PLGA, and their copolymers, including tissue responses, degradation mechanisms, and drug-release models. - Highlight PLA/PLGA-based micro- and nanoparticle systems for advanced biomedical applications. - Summarize applications in vaccine delivery, drug delivery, and gene delivery. - Discuss surface modification, PEGylation, and targeting strategies that extend PLA/PLGA utility.

Delivery system: Polymers: Poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA); PLA has D- and L-forms (PDLA, PLLA), while PLGA is a copolymer of D,L-lactic acid and glycolic acid. - Particle types: Micro- and nanoparticles (MPs/NPs). - Payloads: Small-molecule drugs, proteins/peptides, antigens/immunomodulators, and nucleic acids including pDNA, mRNA, siRNA, and microRNA. - Fabrication approaches: Double-emulsion solvent evaporation for direct nucleic acid encapsulation; pre-cationization with cationic polymers for gene delivery. - Cationic agents for gene delivery: PEI, chitosan, polyarginine, pDMAEMA, DOTAP/DOTMA, DC-Chol, and cationic cell-penetrating peptides. - Surface modification/targeting: PEGylation for stealth; ligand coupling with peptides, antibodies, and nucleotides; surfactant/lipid coating.

Approach: Review of in vitro and in vivo literature from the last decade. Covers preclinical models for cancer, inflammation, vaccination, and gene delivery, with various administration routes including SC, IM, IV, pulmonary, intranasal, intravitreal, intraparenchymal, intratracheal, intracochlear, oral, and intradermal. No new primary experiments are reported.

Key methods: Degradation characterization: GPC, TOF-SIMS, DSC, TGA, HPLC, FTIR, NMR, Raman spectroscopy, SEM, AFM, and pH monitoring. - Biocompatibility assessment: In vitro and in vivo testing, tissue-response histology, macrophage/phagocytosis studies, fibrous encapsulation, and inflammation evaluation. - Drug-release modeling: Second-order hydrolysis kinetics, autocatalysis equations, diffusion/erosion models, and particle-size distribution models. - Particle characterization: Size, morphology, drug loading, entrapment efficiency, and release profiles.

Key results: PLA and PLGA are biocompatible and biodegradable; they hydrolyze to lactic and glycolic acids, enter the Krebs cycle, and are eliminated as CO₂ and water. - Degradation is influenced by molecular weight, crystallinity, chemical composition, water uptake, porosity, pH, and additives. Higher molecular weight slows degradation; crystalline regions resist degradation; acidic/basic conditions accelerate it; autocatalysis can create hollow cores. - Three degradation pathways are described: surface degradation, bulk degradation, and bulk degradation with autocatalysis. PLA/PLGA degrade with second-order kinetics depending on ester bond and water concentration. - Drug release from PLA/PLGA matrices is governed by surface and bulk diffusion plus matrix erosion. - Tissue response involves inflammatory response organization, monocyte migration/macrophage differentiation, fibrous capsule development, and fibrous encapsulation. PEGylation and anti-inflammatory drug loading can reduce these responses. - PLGA particles smaller than 10 µm are readily phagocytosed by immune cells. - Applications include vaccine delivery, cancer and anti-inflammatory drug delivery, pulmonary and brain/liver targeting, and gene delivery of pDNA, mRNA, siRNA, and microRNA.

Interpretation: PLA and PLGA are promising for local and systemic therapeutic applications because of their biocompatibility, biodegradability, and tunable degradation. Their degradation can be traced and modeled, and it affects drug-release kinetics. The authors suggest that technology transfer of new PLA/PLGA delivery systems may soon reach clinics, particularly in vaccination and cancer immunotherapy.

Limitations: This is a review, not a primary study; no new experimental data or meta-analysis. - Many specific quantitative outcomes are in tables that are not fully extractable from the provided text. - Studies across the field are heterogeneous in methods, models, and endpoints, limiting direct comparison. - Long-term safety, immunogenicity, scalable manufacturing, and regulatory issues are not deeply addressed. - Clinical data are limited; most discussed applications remain preclinical.