Release of Nano- and Microplastics from Knee Prostheses: A Review of the Emerging Risks and Biomedical Implications

Abstract

Contemporary knee prostheses rely predominantly on a metal–polyethylene bearing couple, which—despite substantial advances in material engineering—continues to generate polymeric wear particles over time. While the local biological effects of polyethylene debris, such as inflammation and osteolysis, are well-characterised, their potential systemic implications remain insufficiently explored. In this review, we synthesise multidisciplinary evidence to evaluate the generation, biological behaviour, and systemic dissemination of polyethylene-derived nano- and microplastics (NMPs) released from knee prostheses. We also contextualise prosthetic wear within the broader toxicological framework of NMP exposure, highlighting translocation pathways, interactions with immune and metabolic systems, and potential multi-organ effects reported in recent experimental and clinical studies. Current findings suggest that prosthetic wear may represent an under-recognised internal source of NMP exposure, with possible implications for long-term patient health. A clearer understanding of the systemic behaviour of prosthetic-derived NMPs is essential to guide future biomonitoring studies, improve prosthetic materials, and support the development of safer, more biocompatible implant designs.

1. Introduction

Knee osteoarthritis (KOA) is a chronic degenerative disease of the femorotibial and femoropatellar joints that causes pain, functional limitation, and substantial disability worldwide [1,2,3,4,5,6,7]. Diagnostic criteria, imaging approaches, and radiographic grading systems for KOA are well-established and have been extensively reviewed elsewhere [8,9,10,11], so here we focus only on the aspects that are most relevant to total knee arthroplasty (TKA) and implant wear. In advanced stages, when conservative management fails, total knee arthroplasty (TKA) is a well-established and successful option that restores joint function and quality of life for millions of patients [12].

Modern TKA relies predominantly on a cobalt–chromium femoral component, articulating against an ultra-high-molecular-weight polyethylene (UHMWPE) tibial insert. Despite major improvements in material design and processing, mechanical loading and cyclic wear inevitably generate UHMWPE wear particles over the lifespan of the implant. Locally, these polymeric particles are known to trigger macrophage activation, chronic inflammation, osteolysis, and, ultimately, aseptic loosening, representing a leading cause of mid- and long-term implant failure [13,14].

Beyond these well-described periprosthetic reactions, the potential for wear-derived nano- and microplastics (NMPs) to disseminate systemically from the joint space has received far less attention. In contrast, most research on NMPs has focused on external exposure pathways such as ingestion or inhalation of environmental plastics, including their detection in human blood, lung, placenta, and other organs [15,16,17,18,19,20,21,22]. Polyethylene wear particles generated by TKA constitute a distinct, internal exposure route, originating directly within the body and potentially bypassing some of the barriers that limit the uptake of environmental NMPs.

In this narrative review, we bring together concepts from orthopaedics, materials science and toxicology to achieve the following: (a) summarise key biomaterials used in knee prostheses and their wear characteristics; (b) describe the pharmacokinetic behaviour of prosthetic-derived UHMWPE NMPs, with particular emphasis on their liberation, translocation, and potential systemic dissemination; and (c) integrate current experimental and clinical evidence on multi-organ effects of NMPs within a framework that highlights the specific internal exposure pathway arising from knee prostheses. By framing prosthetic wear as a source of systemic nano- and microplastic exposure, we aim to support future biomonitoring and mechanistic studies, and to inform the development of safer implant materials and designs.

2. Joint Prostheses and Biomaterials

Total joint arthroplasty has evolved into a family of modular implants that typically combine metallic components, UHMWPE bearing surfaces and, in many cases, polymethylmethacrylate (PMMA) bone cement, with iterative improvements aimed at enhancing durability and reducing wear [23,24]. Currently, the most widely used materials in knee prostheses are cobalt–chromium–molybdenum (Co–Cr–Mo) and titanium (Ti) alloys, UHMWPE in different formulations, and ceramics such as alumina or zirconia [24]. During in vivo service, these components can release a heterogeneous mixture of polymeric (UHMWPE and PMMA [25,26], metallic (Co–Cr–Mo and Ti), and ceramic (alumina, zirconia) wear particles, together with dissolved metal ions, into the periprosthetic microenvironment [26,27,28]. Polyethylene is the second most widely used material after metals. In knee prostheses, although different bearing couples have been explored, the metal–polyethylene bearing couple has consistently shown superior durability, mechanical strength, and clinical outcomes. Polyethylene is a thermoplastic polymer, and the most commonly used type in joint prostheses is UHMWPE: a semicrystalline polymer composed of long ethylene chains.

The main advantages of UHMWPE include high wear resistance, ductility, and fracture toughness, which allow it to absorb stress without cracking; low friction against metals and ceramics; good conformability and processability, enabling precise machining or moulding; the possibility of manufacturing tibial inserts in a variety of geometries and thicknesses; and good biocompatibility [24]. These characteristics have made the metal–polyethylene bearing couple the gold standard for knee prostheses. Consequently, much research has focused on improving the properties of this polymer to reduce wear and particle release [14,25]. The morphology and composition of UHMWPE wear particles, as well as their relationship to specific wear mechanisms, have been extensively characterised using scanning electron microscopy (SEM) coupled with energy-dispersive X-ray spectroscopy in hip and knee implant studies [29] (see Supplementary Figure S1: representative image of the basic structure of total knee arthroplasty prostheses, consisting of a metal–polyethylene friction pair).

Over time, different generations of UHMWPE have been developed, each showing improved performance in terms of wear resistance and microparticle release [14,25]:

• Conventional polyethylene (conventional UHMWPE): Traditionally sterilised with gamma radiation in air, which induces the formation of free radicals and oxidation, resulting in mechanical degradation and increased long-term wear.
• First-generation highly cross-linked polyethylene (HXLPE): Introduced in the 1990s and produced through irradiation to induce cross-linking, significantly improving wear resistance compared with conventional UHMWPE, but at the cost of reduced toughness and fracture resistance [14,25]. Free-radical formation during irradiation can lead to oxidation if not adequately controlled by subsequent thermal treatments (remelting or annealing).
• Second-generation HXLPE: Incorporates modifications such as the addition of antioxidants (e.g., vitamin E) or sequential irradiation combined with thermal treatments. These strategies aim to maintain low wear rates, improve oxidative stability, and preserve mechanical properties, thereby reducing the risk of long-term fracture and oxidation, as demonstrated by simulator studies and clinical follow-up of highly cross-linked and vitamin-E-stabilised UHMWPE in hip and knee arthroplasties [14,25,30,31] (see Supplementary Figure S2: prosthesis placement in a patient).

Beyond UHMWPE, knee prostheses also generate non-polymeric wear particles. As mentioned, Co–Cr–Mo and Ti alloys can release both solid particulate debris and dissolved metal ions as a result of mechanical wear and corrosion processes at articulating or modular junctions [24]. Metallic particles are typically irregular, with sizes ranging from the submicrometre to several micrometres, and may coexist with elevated local concentrations of Co, Cr, or Ti ions. Experimental and clinical studies show that these metallic nano- and microparticles are readily taken up by macrophages and other immune cells, driving chronic inflammation, particle-induced osteolysis and, in some patients, adverse local tissue reactions (ALTR) and regional lymphadenopathy with histiocytosis [24,27,28,32,33]. Thus, while UHMWPE debris remains the predominant driver of classical wear-induced osteolysis in metal–polyethylene total knee arthroplasty, metallic wear and corrosion products represent an additional, clinically relevant source of biological activity around joint prostheses [26].

Ceramics such as alumina or zirconia are used as alternative bearing or coating materials because of their excellent hardness, low friction, and chemical stability [24]. Their wear rates are generally lower than those of metals and polyethylene; however, when ceramic wear, chipping, or fracture occurs, it tends to generate very hard, angular particles that can act as third bodies and contribute to local mechanical damage of surrounding tissues and counterface materials [34]. Similarly, PMMA bone cement can produce polymeric but non-UHMWPE fragments when the cement mantle cracks, undergoes fatigue under cyclic loading, or is mobilised during micromotion. These relatively larger, irregular particles have been implicated in foreign-body granulomatous reactions and osteoclast activation, and they participate, together with metallic and polyethylene debris, in the periprosthetic inflammatory cascade and third-body wear processes [24,26,35].

In this review, we focus specifically on UHMWPE as a source of nano- and microplastic particles because it constitutes the main bearing material in contemporary total knee arthroplasty and the most plausible contributor to chronic internal NMP exposure from the joint itself. Nevertheless, metallic, ceramic, and cement-derived wear particles share similar pathways of periprosthetic translocation, lymphatic drainage, and potential systemic dissemination, and they participate in overlapping inflammatory and immune mechanisms [26,28,36]. Understanding the behaviour of UHMWPE-derived NMPs should therefore be viewed within this broader context of mixed prosthetic debris, while the following sections concentrate on molecular- and organ-level responses that are largely independent of the initial route of entry once particles have reached the circulation.

3. Release of Micro-/Nanoplastics as Wear Particles/Debris: Pharmacokinetic Considerations

First, it is important to clarify the terminology, which varies across disciplines. In orthopaedics, the term “debris” is commonly used to describe the wear particles generated during long-term use of a prosthesis, including metallic, ceramic, and polymeric fragments [25]. In this review, we focus specifically on polyethylene wear particles and, where appropriate, refer to them as micro- or nanoplastics. Following recent proposals, microplastics (MPs) are pragmatically defined as plastic particles with characteristic dimensions between approximately 1 µm and 5 mm, whereas nanoplastics (NPs) are smaller than about 1 µm [37,38]. Because size distributions can span both domains and definitions are not yet fully standardised, we use the umbrella term nano- and microplastic particles (NMPs) throughout [39].

Once released into the joint space, polyethylene particles initiate a complex interaction with the biological environment, which can be analysed by using a framework similar to the pharmacokinetic LADME model (liberation, absorption, distribution, metabolism, and excretion) to facilitate their study and understanding.

• Liberation and Absorption: Polyethylene particles are liberated by cyclic wear of the metal–polyethylene bearing couple under repeated joint loading. Once released into periprosthetic tissues, submicrometre and nanoscale NMPs (typically <1 µm, and particularly <100 nm) can cross cellular and tissue barriers, initiating systemic translocation [39]. In the context of a knee prosthesis, the most relevant translocation pathway is uptake by macrophages, followed by drainage through periprosthetic lymphatic vessels [30,31].
• Distribution: After phagocytosis, NMP-laden macrophages can migrate from periprosthetic tissues into regional lymphatic channels and accumulate in draining lymph nodes. Classic histopathological reports, such as the series by Baslé et al. [32], describe sinus histiocytosis and lymphadenopathy mimicking tumour-like lesions in patients with joint replacements. Once within the lymphatic circulation, experimental in vivo models and limited human observations suggest that NMPs may enter the bloodstream and disseminate systemically [15,32,39,40,41]. Proof-of-principle evidence comes from early-generation hip and knee arthroplasties, where polyethylene particles have been detected in the liver, spleen, and abdominal lymph nodes at autopsy [40]. Although these implants pre-date contemporary low-wear UHMWPE formulations, they demonstrate that prosthetic debris can cross beyond the joint compartment. More broadly, studies on environmental NMP exposure show the distribution to the liver, spleen, kidney, brain (including translocation across the blood–brain barrier), placenta, and reproductive tissues [15,41], supporting the biological plausibility that prosthetic-derived NMPs could follow similar systemic trajectories. Although this subsection focuses on UHMWPE-derived NMPs, metallic and ceramic wear particles generated by prosthetic components are expected to follow similar lymphatic and vascular routes of translocation and have well-documented local and systemic effects in the orthopaedic literature [26,27,28].
• Metabolism: NMPs are synthetic materials that lack effective endogenous metabolic pathways for degradation in humans. Their persistence is due to their chemical resistance and stable structure. Although they may undergo surface oxidation or abiotic degradation (photodegradation, thermal oxidation, and hydrolysis), these pathways do not ensure their elimination from the human body [15,42]. Degradation depends on factors such as particle size, charge, additives, and the local environment (e.g., enzymatic milieu, pH, microbiota).
• Excretion: Elimination pathways for systemically distributed NMPs in humans are still poorly characterised. Microplastics have been detected in human faeces, indicating at least partial gastrointestinal clearance of ingested particles [43]. Recent studies also report polymeric fragments in human urine and kidney tissue, suggesting renal filtration and urinary excretion for a subset of circulating particles [44,45]. Additional off-loading routes may include biliary secretion into the gut lumen and, in women, transfer via placenta, amniotic fluid, and breast milk, which simultaneously contributes to foetal or neonatal exposure [41,46,47,48,49,50,51]. However, the efficiency and size selectivity of these excretory pathways remain uncertain [15]. Prolonged tissue retention, together with NMP-induced intestinal dysbiosis, metabolic disturbances, and structural damage, underscores excretion as a key unresolved component of NMP toxicokinetics in humans.

In terms of particle size, it has been reported that particles smaller than 0.05 µm do not trigger a detectable inflammatory response, whereas those larger than 10 µm cannot be efficiently phagocytosed [14]. Particles within this intermediate range are readily engulfed by macrophages and trigger the inflammatory cascade that leads to osteolysis. Importantly, the size distributions reported for UHMWPE wear particles from TKA fall largely within this bioactive window, linking prosthetic wear directly to periprosthetic inflammation and aseptic loosening [13,14].

From a pharmacokinetic perspective, these wear processes act as a chronic, low-dose liberation source: despite improvements in UHMWPE formulations, the ongoing generation of submicron- and micron-sized particles over years of service remains a leading cause of mid- and long-term TKA failure through particle-induced osteolysis and aseptic loosening [13,14]. The same particle release that compromises local implant longevity therefore also results in sustained internal exposure to NMPs, which is explored in the following sections. Simulator and retrieval studies have consistently shown that conventional gamma-sterilised UHMWPE exhibits substantially higher volumetric wear than first-generation HXLPE, whereas second-generation HXLPE and vitamin-E-stabilised formulations achieve markedly reduced, but still measurable, wear rates [14,25,30,31]. Even at these lower wear levels, the continuous articulation of the joint over years to decades results in the generation of very large numbers of nano- and microparticles, making UHMWPE a persistent internal source of NMP exposure throughout the functional lifespan of the implant. From a toxicological perspective, this scenario is better conceptualised as sustained, low-dose exposure rather than as an isolated, high-intensity event.

Particle-induced osteolysis is a low-grade chronic inflammatory reaction caused by the phagocytosis of polyethylene microparticles by macrophages. These activated cells secrete proinflammatory cytokines (IL-1, TNF-α, IL-6) and osteoclast-stimulating factors (RANKL) which induce periprosthetic bone resorption, particularly in areas of reduced stress. Osteolysis is asymptomatic in its early stages but can progress to mechanical loosening, instability, and even periprosthetic fractures, representing a common cause of revision surgery in younger patients or those with high functional demands. The generation of submicron-sized wear particles, although reduced with HXLPE, can provoke reactive synovitis due to persistent synovial activation. This inflammation contributes to increased joint fluid volume, recurrent effusions, mechanical pain, and loss of range of motion, and it may also complicate the differential diagnosis with subacute prosthetic infections [13].

Integrating these LADME components necessarily combines limited in vivo data from patients with joint replacements, particularly studies of older-generation implants, with more extensive in vitro and animal models of environmental NMP exposure [15,39]. While the former demonstrate that prosthetic debris can disseminate beyond the joint, the latter provide mechanistic insight into barrier crossing, organ tropism, and elimination. This highlights important gaps for contemporary TKA, underscoring the need for dedicated in vivo studies and physiologically based kinetic models tailored to prosthetic-derived NMPs.

4. Molecular and Systemic Effects of Nano- and Microplastics (NMPs)

Although most experimental and epidemiological data on NMPs toxicity derive from inhalation or oral exposure scenarios, the organ systems and biological pathways involved are largely independent of the original route of entry. In the context of TKA, systemic exposure does not originate from the external environment but from the continuous release of UHMWPE wear particles at the implant interface, with subsequent access to the lymphatic system and bloodstream. This section therefore does not aim to review environmental exposure to plastic particles in general, but specifically to outline the potential target organs and mechanistic pathways that may become relevant once polyethylene NMPs generated by TKA enter systemic circulation.

4.1. Molecular and Cellular Mechanisms of NMP Toxicity

At the cellular level, NMPs interact with biological systems through a combination of physical, chemical, and immunological mechanisms. Following contact with biological fluids, plastic particles rapidly acquire a dynamic “bio-corona” composed of adsorbed proteins, lipids, metabolites, and microbial components, which modifies surface chemistry, determines cellular recognition, and can prolong particle retention [52,53,54,55]. Cellular uptake of NMPs occurs mainly via endocytosis and phagocytosis; internalised particles accumulate in endo-lysosomal compartments, where they can cause lysosomal membrane destabilisation, enzyme leakage, and impaired autophagic flux [56,57,58].

These events converge on redox imbalance and mitochondrial dysfunction. Experimental models consistently show that NMPs increase reactive oxygen and nitrogen species, depolarise mitochondrial membranes, and disrupt oxidative phosphorylation, leading to ATP depletion and activation of redox-sensitive signalling pathways such as NF-κB, MAPKs, and cGAS–STING [56,58,59,60,61]. Persistent mitochondrial stress promotes apoptosis, pyroptosis, and, in some organs, ferroptosis characterised by iron accumulation, lipid peroxidation, and glutathione peroxidase-4 depletion [62,63,64]. In immune cells, NMPs act as persistent stimulants, driving NLRP3 inflammasome activation; IL-1β, IL-6, and TNF-α release; and M1 macrophage polarisation, with subsequent tissue inflammation and fibrosis [56,57].

Endocrine and metabolic disruption represent additional mechanistic layers. Plastic polymers and their additives can interfere with hormone receptor signalling, steroidogenesis, and nuclear receptor activation, acting as endocrine-disrupting agents [37,53,65,66]. NMP-induced dysbiosis and increased intestinal permeability further facilitate the translocation of microbial products and plastic-associated chemicals into the circulation, amplifying systemic oxidative stress and inflammatory and metabolic disturbances [27,67,68,69]. Together, these molecular events provide a mechanistic framework linking NMP exposure to the organ-level cardiovascular, respiratory, gastrointestinal, immune, renal, neurological, and reproductive effects summarised in the following subsections.

4.2. Cardiovascular and Vascular System

Human biomonitoring data increasingly point to the role of NMPs in vascular pathology. Polymers such as polyethylene terephthalate (PET), polystyrene (PS), polyethylene (PE), and PMMA have been quantified in human whole blood using pyrolysis–gas chromatography–mass spectrometry [20], with subsequent studies characterising polymer types, concentrations, and size distributions in larger cohorts, using micro Fourier transform infrared spectroscopy (μFTIR) and pyrolysis-based methods [21,22]. Computational modelling suggests that nanoscale plastics deposited in alveoli may translocate into systemic circulation, linking inhalation exposure with cardiovascular deposition and risk [70].

Compelling clinical evidence was provided by Marfella et al. (2024) [71], who identified polyethylene and polyvinyl chloride (PVC) fragments within carotid atheromatous plaques from patients with asymptomatic stenosis. Presence of these particles was associated with a 4.5-fold higher risk of myocardial infarction, stroke, or death over 34 months, alongside increased inflammatory markers. Supporting this, Yang et al. [72] detected microplastics in all 101 patients with acute chest pain, with concentrations being significantly higher in those with acute coronary syndrome and myocardial infarction. The microplastic burden (dominated by PE, PVC, PS and PP) correlated with coronary complexity scores and elevated proinflammatory cytokines (IL-6, IL-12p70) and immune cell activation.

Mechanistic reviews emphasise that NMPs accumulate in vascular tissues where they induce oxidative stress, mitochondrial dysfunction, apoptosis, and fibrosis, contributing to endothelial injury, cardiac remodelling, and elevated risk of major adverse cardiovascular events [73,74,75]. It remains uncertain as to whether plastic particles circulate freely in plasma or are transported by immune cells, raising critical questions about their role in translocation and immune regulation [20].

Although these studies mostly involve environmental NMPs, polyethylene particles released from knee prostheses could, in principle, follow similar vascular pathways once in the circulation, particularly in patients with long-standing implants [74].

4.3. Respiratory System

In environmental and occupational settings, inhalation represents a critical exposure pathway for nano- and microplastics (NMPs). Microplastics have been identified in human lung samples using μFTIR spectroscopy, confirming persistence within the pulmonary environment [76]. Computational and in silico models show that deposition is strongly determined by particle size and shape and airflow dynamics: fibrous and irregular particles demonstrate prolonged airway residence, while nanoscale plastics penetrate deeply into alveolar regions and can cross into systemic circulation [70,77,78]. Although this pathway is not directly relevant to patients with permanently implanted joint prostheses, these data help identify potential pulmonary targets once prosthetic-derived particles have reached the lungs via the bloodstream.

MPs and NPs differ markedly in behaviour. MPs deposit in upper airways by impaction, eliciting mechanical irritation. NPs behave like ultrafine particulate matter, exhibiting prolonged suspension, deeper alveolar penetration via diffusion, and greater potential for systemic translocation [52,78]. Their nanoscale size enables cellular internalisation through endocytosis and mitochondrial interaction, triggering oxidative stress, inflammation, and metabolic disruption [53,59,60]. Consequently, NPs require distinct toxicokinetic consideration, as their capacity for cellular interaction far exceeds that of larger MPs [79,80]. These mechanistic features are expected to depend largely on particle size and surface properties and may therefore also apply to polyethylene wear-derived NMPs entering the pulmonary microvasculature after systemic dissemination from total knee arthroplasty.

Experimental inhalation studies show that polystyrene NPs induce chronic obstructive pulmonary disease (COPD)-like injury in mice, characterised by alveolar inflammation, mitochondrial dysfunction, endoplasmic reticulum stress, and ferroptosis [81,82]. Human in vitro evidence shows polystyrene NPs penetrate bronchial smooth muscle and airway epithelial cells, significantly depressing oxidative phosphorylation and glycolysis, with more pronounced effects in asthmatic cells [59]. Reviews emphasise mitochondria as central targets, linking mitochondrial depolarisation, lipid peroxidation, and ROS overproduction to chronic respiratory pathologies, including COPD and idiopathic pulmonary fibrosis [83].

Occupational evidence is consistent: workers in the synthetic textile, flocking, and plastic-processing industries develop chronic respiratory symptoms, airway obstruction, and interstitial lung disease associated with long-term inhalation of airborne synthetic microfibres and plastic dust [84,85,86]. A systematic review reports indoor air as the major source of inhaled MPs, with the highest exposure doses being in infants and children [77]. Although quantitative dose–response relationships in humans remain to be established, the convergence of human tissue detection, occupational observations, and mechanistic evidence highlights the credible risk of chronic respiratory morbidity. Further longitudinal biomonitoring and epidemiological studies are urgently needed [41,77].

In the context of arthroplasty, inhalation is not a primary exposure route; however, data on inhaled NMPs provide important mechanistic insight into how systemically translocated prosthetic-derived particles might interact with the pulmonary microvasculature and contribute to cardiopulmonary risk.

4.4. Gastrointestinal, Hepatic, and Metabolic Effects

The gastrointestinal tract constitutes a major entry route for NMPs, with consequent local and systemic effects. NMPs can cross the epithelium via endocytosis, persorption through Peyer’s patches, and paracellular transport, with subsequent biodistribution to the liver, kidney, spleen, and brain [15]. Following ingestion, NMPs impair epithelial integrity, increase intestinal permeability, and induce mucosal inflammation, alongside alterations in the gut’s microbial composition, resulting in dysbiosis and perturbed metabolites [67]. Intestinal dysbiosis and barrier failure facilitate the translocation of microbial products and plastic-associated compounds to the liver via portal circulation, triggering oxidative stress, inflammatory activation, lipid metabolic disturbance, and early steatotic changes [68].

In mice, prolonged exposure to polystyrene particles (20 nm–5 µm) caused accumulation within intestinal villi, reduced tight-junction proteins and mucins, increased intestinal permeability, enhanced lipopolysaccharide translocation, leukocyte infiltration, and significant dysbiosis. These adverse effects intensified as the particle size decreased and exposure lengthened, highlighting NPs as the most bioactive fraction [36]. Combined dietary and MP exposure models show synergistic damage to intestinal structure, redox balance, and microbial composition, coupled with increased hepatic steatosis and inflammatory infiltration. Cessation of high-fat diet alone partially restored gut and liver function, whereas simultaneous cessation of both diet and MP exposure produced limited recovery, suggesting that prior MP ingestion impairs the restitution of barrier and microbiota homeostasis [69].

Larger MPs tend to remain in the gut lumen, interfering mechanically with digestion and disturbing nutrient absorption. NPs possess greater surface reactivity and mobility, enabling close epithelial interaction and systemic translocation via paracellular and endocytic pathways [15,65]. Their nanoscale dimensions enhance ability to adsorb organic pollutants, metals, and microbial components, forming bioactive coronas that modulate host–microbe and immune interactions, exacerbating oxidative stress, inflammatory signalling, and microbial dysbiosis [52,53]. Disruption of epithelial integrity and microbial balance facilitates the translocation of inflammatory mediators to the liver, promoting hepatic oxidative stress, lipid accumulation, and metabolic dysregulation. Chronic NP ingestion could amplify pre-existing metabolic disorders and contribute to hepatic steatosis or non-alcoholic fatty liver disease, underscoring the systemic significance of gastrointestinal exposure [15].

These findings, although mostly obtained in models of oral environmental exposure, suggest that polyethylene NMPs originating from knee prostheses and reaching the gut–liver axis via the bloodstream could add to the overall internal particle burden and potentially aggravate subclinical intestinal and hepatic inflammation or metabolic dysfunction in susceptible patients.

4.5. Immune System

NMPs act as persistent immune adjuvants, stimulating macrophage activation and sustained cytokine release. Their physicochemical diversity facilitates prolonged interaction with immune cells, activating pattern-recognition receptors and downstream signalling pathways, including NF-κB, cGAS–STING, and NLRP3 inflammasome cascades [56]. Phagocytosed NMPs trigger excessive reactive oxygen and nitrogen species, lysosomal damage, and activation of redox-sensitive signalling, converging on the TLR4/p38/NF-κB and NLRP3 pathways, promoting IL-1β, IL-6, and TNF-α secretion and M1 macrophage polarisation [57]. Prolonged exposure induces macrophage exhaustion and impaired antigen presentation. MPs accumulating in lysosomes resist enzymatic degradation, leading to lysosomal enzyme leakage, mitochondrial dysfunction, and apoptosis [58]. Formation of a dynamic protein or bio-corona modifies the surface chemistry and immune recognition, enhancing phagocytosis and prolonging intracellular retention while acting as danger signals that reprogram innate immune memory [54,55]. A recent scoping review catalogued MP detections across multiple human organs, emphasising the immunotoxic potential and critical gaps in the exposure characterisation required for quantitative risk assessment [87].

While mechanistic studies consistently demonstrate the activation of oxidative and inflammatory pathways, human evidence remains fragmentary. Galluzzi et al. (2025) [88] note that the true immunotoxic potential of MPs in vivo is uncertain, largely due to the absence of harmonised exposure metrics and difficulties quantifying internal doses. Particle size, surface reactivity, and formation of microbial or protein coronas likely determine immune recognition and downstream responses, with NPs displaying greater potential for cellular uptake and inflammation than larger particles. Consequently, improving analytical sensitivity and establishing human-relevant dose–response relationships remain essential for advancing immune risk assessment.

Taken together, these observations are consistent with the well-known role of UHMWPE wear particles as potent activators of macrophages and other innate immune cells, and they support the notion that prosthetic-derived NMPs may act as a chronic, low-dose immune stimulus with both local (periprosthetic) and systemic consequences.

4.6. Renal System

Direct human evidence indicates that the kidney participates in the systemic processing and excretion of microplastics. Pironti et al. (2022) [44] provided the first demonstration of polymeric fragments (polyethylene, polypropylene, PVC, ethylene–vinyl acetate; 4–15 µm) in human urine using Raman microspectroscopy, suggesting that ingested or inhaled MPs pass through the gastrointestinal tract, enter systemic circulation, and are eliminated via the urinary route. Micro-Raman spectroscopy of renal biopsies further detected MP fragments within the kidney parenchyma, establishing both tissue accumulation and urinary clearance pathways [45].

In whole-body inhalation models, polystyrene NPs translocate across the alveolar barrier, accumulate in renal tissue in a time-dependent manner, and induce tubular injury, glomerular proliferation, immune infiltration, mitochondrial swelling, and increased serum creatinine and urea [62]. In vitro, human proximal tubule epithelial cells internalise polystyrene NPs, triggering mitochondrial depolarisation, oxidative stress, and apoptosis [89]. Integrated proteomic and metabolomic data reveal suppression of oxidative phosphorylation and mTORC1-regulated metabolism [61].

Long-term exposure studies identify ferroptosis and ferritinophagy as central pathways. Chronic administration of polystyrene and amino-functionalised MPs at environmentally relevant concentrations led to renal fibrosis in mice, characterised by collagen deposition, inflammatory infiltration, and tubular epithelial detachment, driven by iron accumulation, glutathione peroxidase-4 (GPX4) depletion, and activation of the NCOA4-dependent ferritinophagy axis, culminating in lipid peroxidation and ferroptotic cell death. Pharmacological inhibition of ferroptosis partly restored antioxidant defences and suppressed fibroblast activation [63]. Macrophage–particle interactions amplify renal inflammation: persistent lysosomal retention provokes mitochondrial dysfunction and excessive ROS, activating the NF-κB and NLRP3 inflammasome pathways promoting M1 polarisation and cytokine release [57,58]. Together, these findings provide convergent evidence that NMPs reach and persist within the kidney, triggering oxidative, ferroptotic, and immunoinflammatory disturbances [64].

While most evidence of renal toxicity comes from environmentally ingested microplastics, the same mechanisms of tubular uptake, oxidative stress, and fibrosis could, in principle, operate if polyethylene NMPs released from knee prostheses accumulate in the kidney, following prolonged systemic circulation [90].

4.7. Nervous System

Evidence indicates that NMPs can cross or circumvent classical biological barriers to reach the central nervous system. Detection of polymeric particles in the human olfactory bulb supports an intranasal and axonal translocation pathway bypassing the blood–brain barrier, raising concern about direct neuronal exposure and neuroinflammatory consequences [16]. Polystyrene NPs cross the blood–brain barrier, accumulate in the hippocampus and cortex, and induce oxidative stress, microglial activation, cytokine release, neuronal apoptosis, and cognitive impairment [62,91]. Mechanistically, these effects are mediated by the ROS-dependent activation of ERK-MAPK and HRAS-PERK-NF-κB signalling, mitochondrial dysfunction, and dysregulation of neuronal cuproptosis pathways [92,93]. Behaviourally, exposed animals exhibit anxiety-like behaviour and impaired learning and memory.

Peripheral organ dysfunction, particularly in the gut and liver, may amplify neuroinflammation through circulating cytokines and microbiota–brain interactions, forming a plausible gut–brain axis of NMP-induced neurotoxicity [91]. Animal studies consistently link oxidative stress and neuroinflammatory markers with anxiety-like and cognitive disturbances, suggesting a functional continuum between peripheral and central plastic toxicity [92]. This integrative framework highlights the need for longitudinal human studies incorporating neurocognitive assessment and biomarkers of exposure.

Although direct data for joint-replacement patients are lacking, studies showing that NMPs can cross the blood–brain barrier, trigger neuroinflammation, and impair neuronal function [94] raise the possibility that, over decades of implant wear, prosthetic-derived particles might contribute to cerebrovascular and neurodegenerative processes in highly exposed individuals.

4.8. Reproductive, Developmental, and Endocrine Health

A systematic review reports that most evaluated studies demonstrate placental translocation of plastic particles, highlighting potential foetal exposure [46]. Ragusa et al. (2021) [41] identified twelve pigmented microplastics (5–10 µm) across maternal, foetal, and chorioamniotic compartments, with subsequent investigations confirming polymer fragments in the placental villi, umbilical cord, and meconium, supporting in utero exposure and vertical transfer during gestation [47,62]. A recent targeted risk assessment synthesis reports NMPs on both maternal and foetal sides of the placenta, as well as in amniotic fluid, meconium, and breast milk. Overall, placental risk has been graded as moderate-to-low with the current evidence, but it is likely to increase as particle size decreases, reflecting greater barrier permeability of nanoscale fractions [49].

Human and experimental studies detected polystyrene fragments in chorionic villous tissue, with higher levels in women experiencing unexplained recurrent miscarriage. Gestational exposure to 50 nm polystyrene NPs in mice induced pregnancy loss. Mechanistically, trophoblasts exposed to NPs undergo mitochondrial depolarisation, oxidative stress, and apoptosis, while restoration of Bcl-2 expression attenuated apoptosis and reduced pregnancy loss in vivo [48]. Human placental explant experiments demonstrate time-dependent cytotoxicity and oxidative stress following polystyrene MP exposure, with increased superoxide and hydrogen peroxide generation, depletion of antioxidant defences, accumulation of lipid and protein oxidation products, and broad metabolic reprogramming affecting the tricarboxylic-acid and amino-acid pathways [50].

In pregnant mouse models, exposure to polystyrene NPs impairs endometrial decidualisation by disrupting cell-cycle progression and triggering JNK-MAPK–mediated oxidative stress; pharmacological inhibition of JNK activity partially restored decidualisation and embryo implantation [51]. Comprehensive reproductive toxicology reviews converge on the view that NMP uptake is size-dependent and frequently occurs alongside co-exposure to sorbed contaminants. Mammalian studies implicate these particles in ovarian and testicular injury, endocrine disruption, and impaired gametogenesis, particularly under chronic exposure scenarios, emphasising the need for harmonised exposure metrics and longitudinal human cohorts to establish dose–response relationships that are relevant to pregnancy and developmental outcomes [66].

Beyond reproductive endpoints, these findings also illustrate the endocrine-disrupting potential of NMPs. Experimental studies and recent reviews indicate that plastic particles and associated chemicals can interfere with steroidogenesis, decidualisation, and placental hormone signalling, and may also contribute to broader metabolic and endocrine dysfunction [37,50,51,63]. In the context of polyethylene wear from knee prostheses, such mechanisms are particularly relevant for vulnerable populations (e.g., pregnant individuals and patients with pre-existing endocrine or metabolic disorders) [95], although direct clinical evidence is still limited.

Overall, NMPs can affect multiple organ systems through shared pathways such as oxidative stress, inflammation, and endocrine disruption. A summary of these organ-specific effects and their relevance to polyethylene wear from knee prostheses is provided in Table 1.

Table 1. Summary of potential systemic effects of nano- and microplastics (NMPs) that are relevant to polyethylene wear from knee prostheses, by organ system.

Organ/System	Main Reported NMP-Related Effects	Key Molecular/Cellular Mechanisms	Evidence Base (Humans/Animals/In Vitro)	Potential Relevance for Polyethylene Wear from Knee Prostheses
Cardiovascular and vascular	Endothelial dysfunction, oxidative stress, vascular inflammation, presence of particles in atheromatous plaques, association with higher risk of myocardial infarction, stroke and other major adverse cardiovascular events [20,21,22,71,72,73].	Oxidative stress, mitochondrial dysfunction, disruption of the endothelial barrier, and activation of inflammatory and pro-thrombotic pathways (e.g., NF-κB, inflammasome) [52,70,73,74,75].	Human observational studies (plaques, blood), animal models, in vitro endothelial and cardiac cell systems [20,21,22,70,71,72,73,74,75].	Circulating polyethylene NMPs released from prostheses could interact with vascular endothelium and blood components, potentially contributing to cardiovascular risk in susceptible patients [24,40,71,74].
Respiratory	Lung deposition of microplastics, airway inflammation, COPD-like and fibrotic changes, impaired mitochondrial respiration in airway cells [52,70,76,81,82,83].	Alveolar and airway deposition, ROS generation, mitochondrial damage, ER stress, activation of NF-κB/p38 and other stress pathways [52,53,59,60,70,81,82,83].	Human lung tissue studies, occupational cohorts, animal inhalation models, in vitro airway/bronchial cell models [41,59,76,77,81,82,83,84,85,86].	Direct relevance is limited for arthroplasty-derived NMPs (internal exposure), but respiratory data inform systemic toxicity, dose–response relationships, and potential pulmonary microvascular effects of translocated particles [52,70,77,78,79,80].
Gastrointestinal and hepatobiliary	Intestinal barrier disruption, increased permeability, dysbiosis, mucosal inflammation, hepatic oxidative stress, steatosis, and MASLD-like changes [15,36,67,68,69].	Epithelial damage, altered tight junctions and mucins, bio-corona-mediated uptake, mitochondrial and lysosomal dysfunction, microbiota alterations, gut–liver axis activation [15,36,52,53,65,67,68,69].	Primarily animal models; limited human data (stool, liver markers, microbiome studies) [15,36,43,68,69].	Polyethylene NMPs reaching the liver and gut via the circulation may add to the overall NMP burden processed by the gut–liver axis, potentially contributing to low-grade inflammation and metabolic disturbances in patients with joint prostheses [15,36,43,44,45,68,69].
Immune	Chronic low-grade inflammation, macrophage activation and polarisation, altered innate immune responses, potential immune exhaustion, and impaired antigen presentation [54,55,56,57,58,87,88].	Phagocytosis of NMPs, bio-corona formation, lysosomal damage, NLRP3 inflammasome activation, TLR4/p38/NF-κB signalling, excessive ROS/RNS production [54,55,56,57,58].	In vitro macrophage and immune-cell models, animal studies, emerging human tissue data [54,55,56,57,58,87,88].	Directly relevant to periprosthetic osteolysis driven by UHMWPE wear particles, and potentially to systemic immune activation or modulation in patients with long-standing prostheses [13,24,26,35,56,57,58,87].
Renal	Renal accumulation of particles, tubular injury, glomerular changes, interstitial inflammation and fibrosis, ferroptosis-like cell death [44,45,61,62,63,64,89,90].	Oxidative stress, mitochondrial dysfunction, ferroptosis and ferritinophagy, lysosomal accumulation, activation of inflammatory pathways [57,58,61,62,63,89,90].	Animal exposure models, in vitro proximal tubule cell studies, human urine and kidney biopsy reports [44,45,62,63,64,89,90].	Polyethylene NMPs disseminating from prostheses could accumulate in renal tissue and be partly excreted in urine; although direct clinical evidence is limited, these mechanisms suggest a potential contribution to chronic kidney injury in exposed patients [44,45,62,63,64,89,90].
Nervous	Neuroinflammation, oxidative stress, microglial activation, neuronal apoptosis, behavioural changes, and cognitive impairment in animal models [91,92,93,94].	Blood–brain or olfactory barrier crossing, mitochondrial and ERK/MAPK pathway disruption, ROS production, activation of neuroinflammatory cascades, potential cuproptosis [62,92,93].	Animal models and in vitro neural cell systems; early human tissue evidence (e.g., olfactory bulb) [91,92,93,94].	Relevance to knee prosthesis wear is currently speculative, but if polyethylene NMPs reach the CNS, they could, in principle, contribute to long-term neuroinflammatory and neurodegenerative processes, particularly in highly exposed individuals [91,94].
Reproductive, developmental, and endocrine	Impaired fertility and gametogenesis, placental translocation of particles, adverse pregnancy outcomes (e.g., miscarriage, impaired implantation), endocrine and metabolic disruption, including altered hormone levels and thyroid dysfunction [41,46,47,48,49,50,51,62,66,95].	Oxidative stress, apoptosis and impaired decidualisation, interference with hormone receptor signalling and steroidogenic enzymes, disruption of hypothalamic–pituitary–gonadal and thyroid axes, dysbiosis-related metabolic effects [48,50,51,63,65,66].	Human placenta/meconium/breast-milk studies, animal reproductive and developmental models, in vitro placental and endocrine cell studies [41,46,47,48,49,50,51,62,66,95].	Chronic exposure to polyethylene NMPs from knee prostheses could contribute to the total maternal and endocrine NMP burden, which may be relevant for women of reproductive age or patients with pre-existing endocrine or metabolic disorders, although direct clinical evidence is still scarce [37,50,51,63,66,95].

5. Limitations and Future Directions

Despite the growing experimental and clinical evidence, the understanding of systemic effects arising from prosthetic NMP release remains constrained by methodological and analytical challenges. Quantitative identification of ultra-high molecular weight polyethylene and metallic nano-debris in human biological samples remains technically limited, and the current studies rarely distinguish prosthetic-derived microplastics from environmental microplastics.

A further limitation is the difficulty in distinguishing NMPs derived from polyethylene wear in joint prostheses from those originating from environmental sources such as food, water, or air. Most current human biomonitoring studies do not provide the combination of polymer-specific information, detailed particle morphometry, and temporal linkage to arthroplasty that would be required to reliably apportion sources. In principle, the predominance of UHMWPE or highly cross-linked polyethylene, specific particle size and shape distributions, and their localisation in periprosthetic tissues could support attribution to prosthetic wear, but these criteria have not yet been systematically applied. Future studies integrating joint registries, detailed exposure histories, and high-resolution particle characterisation are needed to differentiate prosthesis-derived NMPs from background environmental exposure.

Future research should prioritise the development of advanced analytical techniques that are capable of detecting and characterising prosthetic-derived NMPs in complex biological matrices. Spectroscopic tools such as μFTIR, Raman microspectroscopy, and pyrolysis–gas chromatography–mass spectrometry are essential to identify polymer types, additives, and metallic components and to distinguish UHMWPE and alloy-derived particles from environmental plastics [20,21,22,44,45,87]. These approaches should be combined with high-resolution imaging methods, including optical and fluorescence microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM), which provide detailed morphometric information (size distributions, aspect ratio, surface roughness) and allow for the recognition of wear-typical morphologies in periprosthetic tissues, regional lymph nodes, and explanted components [6,29,31,45,62,96]. Optical and fluorescence techniques are well-suited to particles in the low-micrometre range and enable high-throughput screening, whereas SEM and TEM extend the detectable sizes into the submicrometre and nanoscale domains, albeit with more demanding sample preparation and smaller fields of view [6,29,31,45,62,96].

Longitudinal biomonitoring studies of patients with joint replacements, integrating these complementary analytical platforms, are needed to assess systemic dissemination and to establish correlations with metabolic, renal, or cardiovascular outcomes [44,45,62]. Comparative toxicokinetic modelling may help to define internal dose–response relationships and to distinguish prosthetic from environmental exposure pathways. Finally, material innovation remains essential: the design of antioxidant-stabilised UHMWPE, surface-engineered titanium and cobalt–chromium alloys, and low-wear hybrid composites could substantially reduce debris generation and improve long-term implant safety [24,25,43].

6. Conclusions

In this narrative review, we have integrated orthopaedic, materials science, and toxicological perspectives to examine nano- and microplastics (NMPs) generated by knee prostheses. Ultra-high-molecular-weight polyethylene (UHMWPE) remains a highly successful bearing material in total knee arthroplasty, but cyclic wear of the metal–polyethylene bearing couple inevitably produces polymeric micro- and nano-debris over the lifespan of the implant. These particles are central to well-recognised local complications, such as particle-induced osteolysis, synovitis, and aseptic loosening.

Evidence from joint-replacement cohorts and experimental models shows that polyethylene and other wear particles can leave the joint compartment via lymphatic drainage, reach regional lymph nodes, and disseminate to distant organs. In parallel, an expanding body of research on environmental NMP exposure demonstrates that such particles can cross biological barriers, accumulate in multiple organs, and trigger oxidative stress, inflammation, immune dysregulation, metabolic disturbance, and endocrine disruption. Taken together, these findings support the view that prosthetic wear is not only a local mechanical problem but also a chronic, low-dose internal source of NMP exposure.

At present, the systemic health implications of prosthetic-derived NMPs remain uncertain. Most mechanistic data come from in vitro and animal models, and current human biomonitoring cannot distinguish prosthetic from environmental plastics. However, the mechanistic parallels between prosthetic debris and environmental NMPs, combined with emerging epidemiological links between NMP burdens and cardiovascular, metabolic, renal, and reproductive outcomes, justify closer scrutiny of long-term implant wear as a potential contributor to systemic disease. Addressing this will require improved analytical methods, longitudinal studies of patients with joint replacements, and further innovation in low-wear, biocompatible implant materials.