PLGA Implants for Controlled Drug Delivery and Regenerative Medicine: Advances, Challenges, and Clinical Potential

Abstract

Poly(lactide-co-glycolide) (PLGA) implants have become a cornerstone in drug delivery and regenerative medicine due to their biocompatibility, tunable degradation, and capacity for sustained, localized therapeutic release. Recent innovations in polymer design, fabrication methods, and functional modifications have expanded their utility across diverse clinical domains, including oncology, neurology, orthopedics, and ophthalmology. This review provides a comprehensive analysis of PLGA implant properties, fabrication strategies, and biomedical applications, while addressing key challenges such as burst release, incomplete drug release, manufacturing complexity, and inflammatory responses. Emerging solutions—such as 3D Printing, in situ forming systems, predictive modeling, and patient-specific customization—are improving implant performance and clinical translation. Emphasis is placed on scalable production, long-term biocompatibility, and personalized design to support the next generation of precision therapeutics.

1. Introduction

PLGA is a pivotal material in biomedical engineering, extensively utilized for its biocompatibility, tunable degradation, and adaptability in drug delivery and tissue engineering. As an FDA-approved polymer, PLGA facilitates sustained and controlled drug release through implants that degrade into lactic acid and glycolic acid—non-toxic byproducts naturally metabolized by the body [1,2,3]. Its versatility, governed by variations in the lactic-to-glycolic acid ratio, molecular weight, and structural modifications, enables the design of implants tailored for diverse therapeutic domains including oncology, endocrinology, orthopedics, and neurology [4,5,6,7].

Critical implant characteristics such as degradation kinetics, drug release profiles, and mechanical performance are modulated through the polymer composition and incorporation of functional additives. Modifications with poly(ethylene glycol) (PEG), poloxamer, and surfactants improve biocompatibility, reduce burst release, and fine-tune release behavior [2,8,9,10,11,12]. These advancements have enabled prolonged drug delivery over periods ranging from days to several months, supporting applications in chronic disease management, localized chemotherapy, and regenerative therapies [6,13,14].

Despite these benefits, PLGA-based implants encounter key limitations. The initial burst release can compromise therapeutic efficacy, especially in sensitive systems such as ocular and neural delivery routes [15,16]. The acidic microenvironment produced during degradation can destabilize labile biomolecules, while high manufacturing costs and technical complexities hinder large-scale production [17,18,19]. Additionally, variability in polymer composition and environmental conditions may lead to inconsistent release profiles, highlighting the need for stringent quality control and predictive modeling to ensure clinical reliability [12,20,21].

This review presents a comprehensive evaluation of PLGA-based implants, emphasizing material characteristics, fabrication strategies, and application-specific progress. It further addresses prevailing challenges and discusses emerging directions aimed at optimizing PLGA systems for improved therapeutic performance. By integrating interdisciplinary insights, this work seeks to foster continued innovation and collaboration across biomedical fields.

2. Essential Materials for PLGA Implant Design

The versatility and efficacy of PLGA-based implants derive from the precise engineering of their constituent materials, including the polymer matrix, therapeutic agents, functional additives, and structural components. Strategic selection and integration of these materials enable the optimization of drug release kinetics, biocompatibility, and mechanical performance across a broad range of biomedical applications.

2.1. PLGA as a Base Polymer

PLGA is a leading biodegradable polymer for implantable systems due to its tunable degradation rate and drug release profile. These properties can be tailored by adjusting the lactic-to-glycolic acid ratio (e.g., 50:50 or 75:25) and molecular weight (15–53 kDa) [1,5,22,23,24,25,26,27,28,29]. A 50:50 ratio typically results in faster degradation and earlier drug release due to higher hydrophilicity and rapid water uptake, making it suitable for applications requiring quick therapeutic onset, such as oncology or anti-infective therapies [22,26,27]. In contrast, a 75:25 ratio slows water ingress and polymer erosion, enabling more prolonged and sustained release, which is beneficial in chronic indications like hepatitis B or ocular delivery [1,5,30].

Further control over degradation kinetics and drug release behavior is achieved through end-group modifications, such as acid and ester end-capping, which influence surface roughness, mechanical strength, and early release rates [21,30]. The LA:GA ratio also affects implant morphology; faster-degrading 50:50 PLGA generates porosity more quickly and lowers local pH through acidic byproducts, which may be suboptimal for sensitive tissues like the inner ear [21]. In such cases, formulations using higher lactic content or PEG-PLGA blends help delay degradation and stabilize the microenvironment [21,24]. Blending PLGA with other biodegradable polymers like polylactic acid (PLA) or polycaprolactone (PCL) enhances mechanical strength and flexibility, broadening its applicability in drug delivery and regenerative medicine [31,32].

2.2. Therapeutic Agents Delivered via PLGA

PLGA-based implants support controlled delivery of a wide spectrum of therapeutic agents. For inflammation-associated disorders, dexamethasone offers prolonged release in ocular and cochlear applications [16,23,33]. Anticancer agents such as doxorubicin, paclitaxel, and cisplatin are incorporated into PLGA systems for localized delivery in cancers, including gliomas and breast cancer [6,13,26,27]. In regenerative medicine, growth factors like basic fibroblast growth factor (bFGF), recombinant human bone morphogenetic protein-2 (rhBMP-2), and vascular endothelial growth factor (VEGF) facilitate angiogenesis, neurogenesis, and osteogenesis when delivered through PLGA-based scaffolds and microspheres [34,35,36]. Additionally, PLGA serves as a delivery matrix for antibiotics, such as amoxicillin and vancomycin, in dental and ocular infections [29,37] and antiangiogenic agents like lupeol and corosolic acid in treating diabetic retinopathy and macular degeneration [38,39].

2.3. Additives, Nanocarriers, and Structural Enhancements

To optimize drug encapsulation, stability, and release profiles, various additives and structural elements are employed. PEG and acetyltributyl citrate (ATBC) are used to regulate flexibility, swelling, and diffusion, thereby improving the overall implant performance [33,40,41]. Stabilizers such as trehalose and beta-cyclodextrin (β-CD) enhance protein stability and hydrophilicity, supporting the delivery of sensitive biomolecules, including monoclonal antibodies [12,42]. In infection-prone environments, antibacterial agents like nanosilver and copper–selenium nanoparticles are incorporated to bolster antimicrobial activity and prolong implant function [43,44,45].

PLGA-based delivery platforms also utilize nanoparticles, microspheres, and scaffolds to achieve localized delivery and regenerative outcomes. Gold nanoparticles conjugated with antagomiR204, for example, enhance osteogenesis in diabetic patients [46]. Similarly, chitosan-based nanoparticles and PLGA microspheres loaded with doxorubicin or exendin-4 improve encapsulation efficiency and therapeutic outcomes in breast cancer and type 2 diabetes mellitus (T2DM)-associated dental applications [47,48].

Scaffolds integrating β-tricalcium phosphate (β-TCP) or hydroxyapatite (HA) with PLGA improve bone regeneration and osseointegration, key for orthopedic applications [32,49]. For cartilage and soft tissue repair, PLGA scaffolds combined with fibrin gels or human embryonic stem cells demonstrate enhanced mechanical stability and regenerative potential [50,51,52].

2.4. Solvents and Processing Aids

The successful fabrication of PLGA implants depends on the use of suitable solvents and processing aids. Hydrophilic solvents such as N-methyl-pyrrolidone (NMP) and glycofurol are essential in in situ forming systems for creating controlled-release matrices [23,53,54]. Dimethyl sulfoxide (DMSO) facilitates rapid solidification in injectable formulations, while agents like triacetin and ethyl heptanoate adjust viscosity and mitigate burst release, contributing to a more predictable and sustained drug release profile [55,56].

Table 1 examines the detailed composition of PLGA-based implants, including additives like PEG, PVA, and excipients. It links composition choices to their effects on implant properties, degradation, and release kinetics. Strategic integration of additives within PLGA systems allows for precise control over key characteristics, such as mechanical stability, biocompatibility, and drug release profiles. Excipients like PEG improve hydrophilicity, promoting uniform drug release, while surfactants reduce burst effects, ensuring steady delivery. Antimicrobial agents enhance biocompatibility and implant sterilization potential. The choice of lactide-to-glycolide ratios influences degradation times, allowing formulations to be customized for short-term or extended therapies. This table highlights how material design in PLGA implants enables the creation of safe, stable, and effective systems, supporting a range of therapeutic applications.

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Omidian, H.; Wilson, R.L. PLGA Implants for Controlled Drug Delivery and Regenerative Medicine: Advances, Challenges, and Clinical Potential. Pharmaceuticals 2025, 18, 631. https://doi.org/10.3390/ph18050631

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