A New Approach to Manufacturing Oral Drug Delivery Systems via Selective Laser Sintering with Water-Insoluble Biocompatible Thermoplastic Polymers: Gaps, Risks, Challenges, and Future Directions

A New Approach to Manufacturing Oral Drug Delivery Systems via Selective Laser Sintering with Water-Insoluble Biocompatible Thermoplastic Polymers: Gaps, Risks, Challenges, and Future Directions | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 18 October 2025 V1 Latest version Share on A New Approach to Manufacturing Oral Drug Delivery Systems via Selective Laser Sintering with Water-Insoluble Biocompatible Thermoplastic Polymers: Gaps, Risks, Challenges, and Future Directions Authors : Klara Maria Dorożyńska 0009-0000-0884-1603 , Ewelina Baran , Przemysław Dorożyński 0000-0001-6835-2916 [email protected] , Grzegorz Formicki , and Piotr Kulinowski 0000-0002-8656-0310 Authors Info & Affiliations https://doi.org/10.22541/au.176075115.59351562/v1 238 views 143 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Selective Laser Sintering (SLS), a laser-based powder bed fusion additive manufacturing technique, has emerged as a promising platform for the fabrication of individualized pharmaceutical dosage forms. This review provides a comprehensive analysis of the usefulness of biocompatible thermoplastic polymers - specifically polyamide 12 (PA12) and polyethylene (PE) - with regards to their physicochemical properties, printability, and functional performance in drug delivery applications. The suitability of these polymers for SLS is assessed in the context of their thermal behavior, structural integrity, and ability to modulate drug release profiles. Emphasis is placed on the toxicological implications of SLS processing, including the formation of volatile organic compounds (VOCs), thermal degradation byproducts, and the generation of micro- and nanoplastics (MNPs), which may pose significant occupational and patient health risks upon inhalation or ingestion. Despite growing interest in SLS-based pharmaceutical manufacturing, critical knowledge gaps regarding the long-term biological fate of these materials, especially under high-energy processing conditions, still persist. The review highlights current regulatory limitations, the absence of standardized pharmacopeial assays, and the challenges associated with powder reuse, sinterability assessment, and emission control. To ensure the safe clinical translation of SLS-fabricated pharmaceuticals, a multidisciplinary approach encompassing material science, toxicology, process engineering, and regulatory science is essential. 1. Introduction Thermoplastic polymers are a class of polymeric materials characterized by reversible thermal transitions: they become moldable or deformable upon heating above their softening or melting temperature and return to a solid state upon cooling. Because of their ability to retain dimensional stability after processing, they are well-suited for precision manufacturing techniques such as micromachining. Thermoplastics can be classified according to their degree of crystallinity, polymerization mechanism, physicochemical properties, or end-use applications; however, the most widely adopted distinction is between amorphous and semi-crystalline polymers. Polyamide 12 (PA12) and polyethylene (PE) are semi-crystalline thermoplastics with physicochemical properties that make them particularly relevant for advanced additive manufacturing techniques, including selective laser sintering (SLS). In SLS, these polymers (processed in powder form) are selectively fused layer by layer, enabling the fabrication of customized drug delivery devices. This approach allows precise control over porosity and mechanical integrity, both of which are critical parameters for tuning drug release kinetics. Among these materials, PA12 is especially valued for its dimensional stability, abrasion resistance, and favorable processing characteristics. Its relatively low melting temperature (ca. 178 °C; 1 ) facilitates the production of complex, patient-specific geometries while maintaining biocompatibility 2 3 , as demonstrated by ISO 10993 compliance and cytocompatibility data 4 . Polyethylene, a widely used semi-crystalline thermoplastic, has more recently gained attention in SLS and other additive manufacturing approaches. Its chemical resistance, processability, and mechanical flexibility position it as a promising candidate for expanding the palette of printable polyolefins. Depending on its density and molecular weight, PE exhibits varying crystallization behaviors, shrinkage tendencies, and porosity during printing, which strongly affect mechanical performance 5 . However, PE’s relatively low laser absorptivity can hinder sintering efficiency. To overcome this limitation, researchers have investigated surface modification strategies and the incorporation of laser-absorbing additives to enhance its SLS performance 6 . In addition, PE’s functional role as an excipient supports the design of matrix-based systems for sustained or delayed drug release, aligning with the goals of personalized medicine. Although PA12 and PE are still rarely employed as excipients in 3D-printed drug delivery systems, their properties suggest strong potential. PA12 supports high drug loading while maintaining structural integrity during dissolution, with release kinetics tunable via printing parameters. PE offers chemical inertness, biocompatibility, mechanical robustness, compatibility with both additive and conventional processing, and the ability to form porous matrices suitable for controlled release. The strategy in pharmaceutical SLS has traditionally been to adapt excipients commonly used in powder compression. However, these materials are optimized for a fundamentally different process and may not perform adequately under the preheating and laser irradiation conditions of SLS. An alternative approach is to explore polymers with properties inherently favorable for this technique. For instance, the first application of a water-insoluble, biocompatible thermoplastic PA12 to fabricate oral dosage forms using SLS was proposed by Kulinowski et al. 7 demonstrating that PA12 can yield high-quality printlets with favorable mechanical performance. While the potential advantages of pharmaceutical additive manufacturing are well documented, the challenges associated with pharmaceutical SLS remain underexplored. In contrast, technical SLS research provides a well-established foundation. Therefore, focusing on polymers with properties specifically tailored for the printing process and drawing on methodologies developed in other scientific disciplines may offer more effective solutions for pharmaceutical applications 8 . Building on these insights, this review critically examines material strategies in pharmaceutical SLS, with particular emphasis on biocompatible synthetic polymers such as PA12 and PE. It further considers emerging toxicological and regulatory challenges, including the formation of thermal degradation byproducts, the release of micro- and nanoparticles, and the risks associated with long-term exposure. By highlighting both the potential and limitations of these materials, the review aims to guide the development of safer and more effective SLS-based drug delivery systems for clinical translation. In this context, the article is presented as a perspective, offering a forward-looking viewpoint that identifies critical knowledge gaps and outlines future directions needed to ensure the safe implementation of water-insoluble biocompatible thermoplastic polymers for manufacturing of drug delivery systems using SLS. 2. Foundations and Development of Additive Manufacturing with a Focus on Selective Laser Sintering 3D printing, widely known as additive manufacturing (AM), involves producing objects by depositing material layer by layer. Designs are created using Computer Aided Design (CAD) software and printed based on data from Standard Tessellation Language (STL) files 9–11 . AM dates back to the 1980s, with the introduction of stereolithography (SLA) by Charles Hull in 1986 12 . Since then, numerous techniques such as selective laser sintering (SLS), laminated object manufacturing (LOM), and fused deposition modelling (FDM) have emerged 13 . These can be categorized by the state of the raw material - powder, solid, or liquid 14 , or, as classified by the American Society for Testing and Materials (ASTM), into seven groups: vat photopolymerization, material jetting, binder jetting, material extrusion, sheet lamination, directed energy deposition, and powder bed fusion 11 . The wide range of AM techniques enables the use of diverse materials, including ceramics, metals, nylon, edible substances, resins, and acrylic photopolymers, with thermoplastics like acrylonitrile butadiene styrene (ABS) and polylactic acid (PLA) being the most common 15 . Since its invention, 3D printing has transformed multiple industries by enabling complex, customizable designs, becoming a cornerstone of the fourth industrial revolution 16 . Selective laser sintering, classified by ASTM as a powder bed fusion (PBF) technique, was developed by Carl Deckard and Joseph Beaman in 1989 17 . It uses thermoplastic powder, that is selectively sintered layer by layer with a laser, fusing particles into complex forms 18–22 . Unfused powder serves as structural support during printing 23 . CO₂ lasers are most commonly used in this technique, although diode and fiber lasers are also applied 11,14 . An SLS printer includes a laser source, powder reservoir, powder bed, and a roller or blade, which spreads powder evenly. The laser sinters it, the bed lowers, and new powder is delivered 24 . Excess powder can be recycled by mixing it with virgin material 25 . The operating principle of SLS printer is presented in Figure1. Figure 1. Operating principle of a selective laser sintering printer for pharmaceutical tablet fabrication. SLS is a versatile AM technique, offering advantages such as powder reusability, lack of or limited pre-processing, and high print resolution 9,17 . Though commonly used with metal powders, it supports a wide range of materials including plastics, composites, ceramics, and polymers - most notably polyamide 12, a cost-effective and easily processible nylon 12,18,23,26 . SLS holds significant potential for application across a wide range of sectors, including aerospace, automotive, dentistry, electronics, engineering, military, medicine, and pharmacy 10,27 . Despite the rapid growth of 3D printing in pharmaceutical manufacturing, SLS remains relatively novel and underexplored in this field 28,29 . However, it has demonstrated promise in producing various drug formulations such as pellets, sustained release, and disintegrating tablets 10,11,30–33 . Compared to techniques like fused deposition modeling, stereolithography, and digital light processing (DLP), SLS enables the direct sintering of pharmaceutical materials without solvents or filament preparation, simplifying the manufacturing workflow 23 . Moreover, the process generally requires no support structures or extensive post-processing, enhancing efficiency and versatility 9,16,20 . These attributes support the rapid production of personalized drug products in various shapes, sizes, and release profiles without the need for equipment changes 17,21 . Among its most promising applications is the advancement of personalized medicine (PM), where SLS supports therapies tailored to patient’s individual characteristics like genetics, age, and lifestyle 10,34 . This aligns with broader healthcare trends such as digital pharmacy and telemedicine, both aiming to improve access to therapeutic care, especially in underserved populations 16 . Since its first reported pharmaceutical application in 2017, SLS has garnered increasing interest 35 with more than 3600 publications concerning SLS and drug delivery through last decade (https://pmc.ncbi.nlm.nih.gov access 12.09.2025). While current research largely focuses on optimizing printing parameters and understanding material behavior 17 , comprehensive evaluations of toxicological and regulatory considerations remain limited and warrant further investigation. 3. Materials and Formulation Strategies for Selective Laser Sintering Selective Laser Sintering is an emerging technology in pharmaceutical manufacturing, enabling the potential fabrication of complex, personalized drug delivery systems. Although it is possible to print tablets with almost pure active substance 36 , the compatibility of pharmaceutical excipients with SLS remains a subject of ongoing investigation. Two primary formulation strategies have been identified: (1) the adaptation of conventional pharmaceutical excipients using classical formulation approaches, and (2) the use of synthetic, biocompatible polymers specifically developed for 3D printing applications. The current trend in Selective Laser Sintering for pharmaceutical applications predominantly involves the adaptation of traditional excipients originally designed for powder compaction. For instance, Seoane-Viaño et al. used various grades of hydroxypropyl cellulose (HPC) in combination with Candurin® Gold Sheen to fabricate MRI contrast agent-loaded printlets 37 . Similarly, Funk et al. developed efavirenz tablets using Parteck® MXP 4–88 and Kollidon® VA64 38 . These studies underscore the adaptability of established pharmaceutical excipients for SLS-based drug formulation. However, they also highlight persistent limitations related to thermal and rheological properties, which often hinder effective sintering. To broaden the range of printable materials, researchers have explored both modified and alternative excipient systems. Abdalla et al. 39,40 formulated tablets containing paracetamol, ibuprofen, and caffeine using blends of ethylcellulose, AQOAT, polyethylene oxide, Eudragit®, and various natural gums 40 . Katsiotis et al. 41 combined Kollidon® VA64 with Candurin® NXT Ruby Red to produce theophylline-containing printlets, while Yang et al. 27 employed polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), and Eudragit® variants in multicomponent systems containing indomethacin and metoprolol. Trenfield et al. 32 investigated the use of Eudragit® L100–55 and HPC for the fabrication of theophylline and itraconazole formulations, and Awad et al. 31 produced dual-API miniprintlets with paracetamol and ibuprofen using ethylcellulose N7 and Kollicoat® IR. Despite these advancements, the printability of conventional pharmaceutical excipients remains a significant bottleneck in the development of SLS-based drug delivery systems. Many of these materials exhibit poor thermal flow behavior, low sinterability, or are prone to degradation under the high-energy conditions required for SLS processing. These limitations compromise the mechanical integrity, resolution, and therapeutic reliability of the final dosage forms, underscoring the need for excipients specifically engineered for additive manufacturing applications. Studies highlight that many standard excipients display poor flow properties at elevated temperature, limited sinterability, or undergo thermal degradation during SLS, which directly impacts the structural and functional quality of printed tablets. In support of this, a study evaluating excipient printability using a CO₂ laser demonstrated that critical material attributes - such as glass transition temperature, degradation onset, particle size, and powder flowability - vary widely among pharmaceutical-grade polymers, rendering only a limited subset truly suitable for successful SLS fabrication 23,42 . An alternative strategy involves the use of synthetic polymers engineered specifically for thermal processing and additive manufacturing. While these materials often exhibit superior printability and mechanical performance, their application in pharmaceuticals necessitates rigorous toxicological evaluation. For instance, polyamide 12 and polyethylene have shown promise due to their high thermal stability and mechanical strength, but their biological behavior under pharmaceutical conditions remains poorly understood. The use of polyethylene with established medical applications illustrates the advantages of employing SLS-dedicated materials in pharmaceutical formulations. In the study by Salmoria et al. 43 , porous PE/fluorouracil ”waffles” were fabricated via SLS for implantable drug delivery in bone cancer treatment. PE provided a thermally stable, biocompatible matrix that enabled both initial burst release and subsequent sustained delivery of fluorouracil. Mechanical properties and porosity were tunable through adjustment of laser power, and spectroscopic and thermal analyses confirmed the absence of chemical interaction between the polymer and drug, preserving the therapeutic integrity of fluorouracil. Building on this work, Salmoria et al. 44 (2018) developed a PE-based intrauterine device (IUD) incorporating both 5-FU and progesterone (PG) for localized gynecological cancer treatment. The SLS-fabricated IUDs exhibited a desirable dual-release profile - rapid diffusion of fluorouracil due to its hydrophilicity, followed by sustained progesterone release governed by zero-order kinetics. Higher laser energy yielded devices with improved mechanical properties due to enhanced polymer coalescence. Spectroscopic and thermal characterization verified the structural integrity and distribution of both active agents without evidence of degradation. Polyamide 12 has been adopted as a reference material in studies of pharmaceutical printing due to its excellent flowability, narrow particle size distribution, and strong laser absorbance, which together ensure reliable sintering and dense, uniform dosage forms 23 . Beyond its role as a benchmark, PA12 has also been directly applied in drug-loaded formulations, for example Kulinowski et al. 7 explored the use of PA12 in creating composite printlets composed of up to 90% crystalline metronidazole embedded within a nylon matrix. PA12 functioned as an inert, insoluble structural excipient, providing mechanical resilience and controlled drug release. These printlets demonstrated sufficient mechanical strength comparable to conventional tablets, floated under gastric conditions due to their porous structure, and allowed for tunable release profiles through formulation adjustments, such as the incorporation of osmotic agents like sodium chloride. The study underscores the value of polymeric composite systems in enabling SLS of highly drug-loaded oral dosage forms. Despite these advances, a critical gap persists in our understanding of how excipients behave under the high-energy conditions of SLS. Conventional safety data do not account for the physicochemical transformations that occur during laser sintering, nor do they address the formation of potentially harmful degradation products. Furthermore, polymers originally intended for industrial 3D printing may fragment into micro- or nanoplastics, raising concerns about systemic exposure and long-term health risks following ingestion or implantation. SLS offers a transformative platform for pharmaceutical manufacturing, enabling control over drug release profiles and dosage form geometry. However, its success hinges on the development of excipients that balance printability with biocompatibility and safety. Bridging the regulatory and scientific knowledge gaps will be essential to unlocking the full potential of SLS in drug delivery and ensuring patient safety in future clinical applications. 4. Occupational and Patient Health Hazards While research has made significant strides in identifying and optimizing excipients for SLS-based pharmaceutical formulations 32,37,38,40 , much of the focus remains on formulation science and printability. However, as the adoption of additive manufacturing technologies in pharmacy continues to grow, it becomes increasingly important to consider the broader implications of this method - particularly its safety profile. Despite promising advancements, the potential risks associated with the SLS process, including emissions and material handling, remain insufficiently explored. This is especially concerning given the scale-up of AM applications and the potential for both occupational and patient exposure to hazardous byproducts. Therefore, beyond formulation efficacy, attention must also be directed toward understanding and mitigating health hazards linked to the use of SLS in pharmaceutical settings 45 . When using insoluble polymers as an excipient in form of powders, as presented by Salmoria et al. 44 and Kulinowski et al. 7 , two powder fractions should be accounted for: original excipient (preprocessed and postprocessed) and residues remaining after dissolving the drug substance from the printed matrix. In Figure 2 potential pathways through which byproducts of 3D printed drugs may infiltrate organisms of the printer operator and the patient are presented. Figure 2. Potential exposure pathways for microplastic and thermal degradation byproducts from 3D-printed pharmaceuticals in operators and patients. 4.1. Toxicological Considerations of Micro- and Nanoplastics Figure 2. illustrates two primary pathways of micro- and nanoplastic exposure: direct release during additive manufacturing processes affecting operators, and the potential formation of MNP residues following drug dissolution in the patient’s digestive tract. To contextualize these pathways, several representative toxicity studies of micro- and nanoplastics are summarized below, highlighting both the underlying mechanisms and the methodological approaches that can guide the design of appropriate protocols for future assessments. Interest in additive manufacturing, particularly 3D printing, has expanded rapidly in recent decades, with polymer-based techniques such as laser powder bed fusion attracting particular attention. Polyamide 12 has emerged as one of the most extensively studied materials in this context, reflecting its growing importance in AM applications 46 . Despite this progress, research addressing the health, safety, and toxicological aspects of AM remains comparatively limited, creating a critical gap in understanding the potential risks associated with polymer processing and exposure 47 . Before delving into these safety concerns, it is important to define two foundational terms: “toxicity” and “biocompatibility.” Toxicity refers to the degree to which a substance can cause nonspecific harm to biological systems, including cells, tissues, or entire organisms. In contrast, biocompatibility is defined by the European Society for Biomaterials (1986) as “the ability of a material to perform with an appropriate host response in a specific application” 48,49 . Contemporary toxicological understanding in AM primarily stems from studies on fused deposition modeling. In this context, emission profiles are influenced by multiple factors, including filament composition, pigment content, printer model, and processing temperature. For instance, ABS filaments release thermally degraded byproducts such as acrylonitrile, 1,3-butadiene, and styrene - compounds with well-documented toxicological significance 50,51 . Selective laser sintering, although less extensively studied in this regard, also involves steps such as powder handling, mixing, and transfer that are associated with the release of dust, ultrafine particles (UFPs), and volatile organic compounds (VOCs). These airborne emissions can be inhaled and subsequently distributed systemically via the bloodstream 15,52–54 .Despite these risks, data concerning the specific chemical composition of these emissions and their long-term health implications remain limited 53 . Particular concern has arisen regarding the generation of nanoparticles and ultrafine particulate matter in AM processes, especially during metal-based printing and powder recycling, where emissions may include toxic metals such as lead, antimony, and selenium 50 . Similarly, polymer-based AM processes are increasingly recognized as sources of micro- and nanoplastics, which represent an emerging toxicological risk. Microplastics (MPs), defined as plastic particles ≤5 micrometers (µm), and nanoplastics (NPs), defined as particles ≤100 nanometers (nm), have been implicated in adverse effects across multiple physiological systems including the gastrointestinal, respiratory, neurological, reproductive, and cardiovascular systems 55–58 . These particles differ widely in polymer type, chemical composition, size, shape, and environmental degradation state - factors that complicate their toxicological assessment and regulatory control 59–61 . As AM technologies advance, the potential for exposure to such particulate matter underscores the need for comprehensive safety evaluations. Nanoparticles, due to their high surface area-to-mass ratio and chemically reactive surfaces, are particularly potent. Their cellular uptake is influenced by shape (with spherical particles more readily internalized) and surface charge - positively charged particles are associated with enhanced cellular entry and increased cytotoxic potential 55,62,63 . MNPs exert toxicity through a network of interrelated molecular mechanisms that disrupt cellular and systemic homeostasis. A key pathway involves the overproduction of reactive oxygen species (ROS), leading to oxidative stress, lipid peroxidation, mitochondrial dysfunction, and DNA damage, which in turn trigger apoptosis, ferroptosis, or mitophagy in diverse cell types 64–68 . These processes are frequently accompanied by inflammatory responses initiated via activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and upregulation of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α). These cytokines are often modulated by toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling cascades 69–72 . MNPs also compromise mitochondrial function, reducing adenosine triphosphate (ATP) production and membrane potential, while promoting mitochondrial DNA (mtDNA) release. This activates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, leading to cellular senescence and immune activation 67,73 . Concurrently, endoplasmic reticulum (ER) stress, often mediated by protein kinase RNA-like endoplasmic reticulum kinase (PERK), exacerbates cellular dysfunction 66,70 . Barrier integrity is another key target of MNP toxicity. These particles reduce expression of tight junction proteins such as zonula occludens-1 (ZO-1) and occludin, compromising the integrity of physiological barriers including the blood-brain barrier, intestinal epithelium, placental interface, and reproductive tract 70 . In neurons, NPs promote the aggregation of alpha-synuclein (α-synuclein) and impair its degradation, thereby contributing to Parkinson-like neurodegeneration 56 . Epigenetic alterations contribute significantly to the toxicity of micro- and nanoplastics. These include dysregulation of long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and aberrant N6-methyladenosine (m6A) methylation, particularly in cardiac and reproductive tissues 74,75 . In parallel, a growing body of evidence highlights the gut microbiota as a key mediator of systemic MNP effects. MNPs have been shown to disrupt microbial homeostasis, increasing the abundance of pathogenic taxa such as Klebsiella, Desulfovibrionaceae , and Enterobacteriaceae , while depleting beneficial groups like Akkermansia , Christensenellaceae , and Akkermansiaceae 76–78 . This dysbiosis has been linked not only to gastrointestinal inflammation but also to impaired immune regulation, disrupted hematopoiesis, and neurodevelopmental deficits via the gut-brain axis 60,79,80 . Toxicological studies in both mammalian models and human cell cultures further confirm that MNPs exert harmful effects across multiple physiological systems - including the digestive, respiratory, nervous, reproductive, and cardiovascular systems - through both direct cellular mechanisms and indirect, microbiota-mediated pathways 55–58 . Moreover, MNPs can act as vectors for microbial pathogens and environmental contaminants, further amplifying their toxic potential and ecological impact 63,74,81 . The summary of cellular and systemic mechanisms underlying the toxic effects of micro- and nanoplastics is presented in Figure 3. Figure 3. Cellular and systemic mechanisms underlying the toxic effects of micro- and nanoplastics. Despite growing awareness, the data on AM-related exposure hazards remains limited - especially regarding the physicochemical properties of emitted particles, byproducts of material extrusion, exposure during post-processing and handling, and the long-term effects of chronic low-dose exposures 15,47 . Most studies to date are focused on engineering applications, with biomedical and pharmaceutical aspects still significantly underrepresented 82 . Furthermore, occupational exposure risks - especially from the use of virgin and recycled powders in SLS - have received little attention. As of 2022, the European Union had not yet established formal occupational exposure limits or personal protective equipment standards for AM environments 47 . 4.2. Occupational safety As of now the best researched health hazards in 3D-printing are the ones related to the FDM of thermoplastic materials. There have been studies concerning the effect of filament type, filament colour, printer type and printing temperature on printer emissions 51 . For example, the most commonly used material, such as ABS, when heated up, creates three toxic decomposition products: acrylonitrile, 1,3-butadiene and styrene 50 . In AM techniques particulate materials are already present in powder feedstocks of printers or can also be created during the printing process. Because of this there is a possibility of exposure to those feedstock particles or AM printer emitted byproducts, as well as chemical fumes emitted, at various stages of production from powder handling to printing post-processing, machine cleaning, and maintenance 47 . Nylon powders, which are materials most commonly used in non-pharmaceutical PBF techniques, while not being particularly hazardous by themselves, have still been found to cause elevation of pulmonary injury parameters and inflammation 83 . These emissions and potential hazards depend on various factors e.g. brand of the printer and materials used, the temperature at which the printing takes place and so on 15,53 . Studies have shown that 3D printing, power bed fusion type in particular, and its preparation processes such as mixing, grinding, transferring and handling powders generates dust, ultrafine particles and volatile organic compounds to which the operators of SLS AM machines are exposed, with particles entering lungs and bloodstream of operators via respiration 15,52,53 . However, little is known about their chemical composition or potential toxicity 53 . Many VOCs are known to be potentially carcinogenic, and the prolonged exposure can lead to headache, eye, nose, and throat irritations, or coordination loss 47 . Another problem, which is connected with 3D-printing emissions, are nanoparticles, which have been a cause of concern for years in various different technologies and industries. There is a lack of models that would allow prediction of potential safety or hazard of a designed nanomaterial, and similarly there is little reliable information about the effects of human exposure to nanoparticles 55 . In other manufacturing methods, mainly in metal manufacturing processes, emission of various unintended particulate matter e.g. VOCs and nanoparticles have been observed. For example, in the process of refining silver there is a substantial number of airborne metal particles and nanoparticles, that apart from silver also include antimony, lead, selenium, and zinc. Similarly, in recycled metals used in selective laser melting (SLM) and SLS, ultrafine PM by-products have been found 50 . 4.3. Patient safety – digestive system This section is particularly crucial, as patient safety may be directly affected by the presence of micro- and nanoparticles in the gastrointestinal tract during different stages of drug release from 3D-printed dosage forms. While the effects of operator exposure to airborne particles generated during 3D printing have been investigated 47,84 , far less is known about the potential consequences of particle ingestion by patients. Due to the inertness of the micro- and nanoplastics, the digestive systems of humans lack capability to decompose these particles. However, they can still have a potentially harmful effect on the digestive track, because when ingested they can affect the physiological functions of the gastrointestinal tract – lipids, proteins and other biological components can adsorb to microplastics, which affects the particle size and shape, but can also affect the digestion of said components e.g. lipids 85 . The research concerning the fate of nanoplastics in human gastrointestinal tract is scarce - in 2021 it was reported that there were no such studies 85,86 . Although microplastics are generally less bioavailable than nanoplastics, in vivo and human studies show that some MPs can translocate beyond the gut and be found in internal organs (e.g., liver), whereas NPs readily cross the gastrointestinal barrier and distribute systemically - including to gastric/intestinal tissues and the liver in mice 87–91 . They can enter the circulatory system and lymphatic tissue, which can lead to immunotoxicity, genetic toxicity, decreased reproductive capacity, decreased survival rate, increased mortality and stunted growth and development. It was also reported that they can cross the blood-to-brain barrier in fish 59,74 Microplastics can be introduced into the circulatory system, although they are later swiftly removed from the circulation 61 . The excretion rate of the polymer particles (as researched in rats) depends on the particle size. Larger microparticles leave the organism quicker than those that are smaller. Some nanoparticles do not leave the body, and can be found in blood, which means they can be absorbed in the digestive tract 59 . There are studies showing that nanoplastics can be accumulated in various organs like liver, lungs, kidneys, gut or brain 92 . Both micro- and nanoplastics can disturb intestinal microbiota and some intestinal functions, as well as cause destruction of intestinal epithelial permeability 74 . Assessment of nanoparticles absorption in human gastrointestinal tract lumen proves precarious since the is a lack of validated methods, certified reference materials and standardization across the analytical procedures used 85 . Another reason is the fact, that nanoparticles can undergo a number of transformations while in the digestive system, as a result of various conditions: high salinity, changes in acidity between the compartments, physiological temperature, presence of digestive juices and interactions with different particles present there i.e. proteins, lipids, carbohydrates, nucleic acids, ions, and water. These may lead to surface changes, fragmentation or agglomeration, which could influence the propensity of nanoparticles to be transported to the intestinal epithelium cells and in turn to various organs 85,86 . The internalization of plastics in the digestive system occurs primarily in the epithelium around Peyer’s patches (in case of smaller particles) or through persorption after crossing the intestinal mucus (in case of larger particles). The ones that are not absorbed are subsequently removed in the feces 61 . 5. Regulatory and Logistical Challenges The printing process requires the use of large quantities of powder in order to ensure consistent layer height and suitable flow of powders, which can cause problems if the drugs are available in limited quantities or if the drug substances are expensive 11 . Another challenge that comes with SLS (but also other 3D printing methods) is recycling the material, as during the printing process only a portion of the powder is sintered 12,17 . As a way to limit wasting of materials, the unsintered powder is often found to be reused in a few production processes. Repeated heating, however, can lead to many concerns, that include size and shape changes of powder particles and thermal degradation. The most common solution to this problem in the industry is using mixtures of virgin and recycled powder, as well as incorporating stabilizing agents, as a way of obtaining more thermally stable material 17 . As indicated by field observations, approximately 50% of the unsintered powder can be recycled efficiently 19 . In literature terms “recycling of powder” and “reuse of powder” are often used interchangeably, however they are not the same processes. Recycling is the production of new atomization feedstock either through remelting scrap materials or through recovering material from other manufacturing methods. Reuse, on the other hand, refers to repetitive using a single batch of powder in multiple subsequent printing cycles until the powder is out of specification or predefined boundaries 47 . In theory, all powders that bond together after heating should be eligible for SLS printing 27 . However, the ability of powder to become sintered, or rather its “sinterability” for short, is a more complex problem in pharmacy, with various factors having to contribute, such as flowability of powder, its compactness and absorbance 27,93 . Even though these factors are individually well understood, it is not the same with them all as a one phenomenon, and therefore there are, as of now, no pre-sintering methods allowing to quickly evaluate if pharmaceutical polymers and formulations are printable 93 . Furthermore, even if the material is “sinterable”, there are no tools to anticipate the anomalies and defects that may appear when using pharmaceutical-grade excipients in SLS (such as: charring, incomplete spreading, under-sintering, part damage and misprint), which leads to a costly, time-consuming trial-and-error way of optimizing the formulations for printing and the need for new materials dedicated for this technology 7,39 . Additionally, the state of knowledge concerning the relationship between the sintering process and the properties of pharmaceutical polymers is also incomplete, apart from establishing if the polymer’s absorbance is compatible with the wavelength of the laser used in the 3D printer 23 . In 2017 Food and Drug Administration (FDA) released guidelines for the AM of medical devices, however no such guidance for 3D printing of dosage forms was presented 11,17 . Additionally, different pharmacopeias also do not have control assays designed for assessing the quality of drug products or biomedical implants produced via 3D printining 11,17 . It has also been established that the manufacturer manuals and associated documentation for AM products tend to lack thorough coverage of health and safety guidelines regarding the materials 45 . 6. Conclusions and Future Directions Selective laser sintering offers transformative opportunities in pharmaceutical additive manufacturing, particularly for fabricating complex, personalized dosage forms with controlled release characteristics. Its ability to process insoluble polymers such as polyamide 12 and polyethylene makes it especially relevant for oral drug delivery systems. However, the findings summarized in this review highlight several critical gaps that must be addressed before SLS can be safely and reliably implemented in clinical practice. A key concern is the toxicological safety of polymers processed under high-energy laser conditions. PA12 and PE, while biocompatible in their bulk form, can undergo physicochemical transformations during sintering that lead to the formation of volatile organic compounds, thermal degradation products, and micro- and nanoplastics. These byproducts pose distinct risks to operators (via inhalation during powder handling and processing) and to patients (via ingestion of residual particles in the gastrointestinal tract). Importantly, in vivo studies have demonstrated that nanoplastics can cross the gastrointestinal barrier, accumulate in organs, and disturb microbiota balance, underscoring the urgency of toxicological investigations specific to SLS-derived pharmaceuticals. Occupational exposure remains insufficiently characterized. Evidence from other AM contexts indicates that repeated handling and reuse of powders alters their morphology and emission profiles, potentially amplifying respiratory risks. Systematic studies on exposure levels in pharmaceutical environments, coupled with workplace mitigation strategies (ventilation, closed powder systems, filtration, and validated PPE protocols), are essential. Patient safety is even less understood. While studies confirm systemic distribution of nanoplastics and partial bioavailability of microplastics, almost no data exists on polymer particles released from SLS dosage forms. Controlled dissolution and digestion models, followed by animal and human pharmacokinetic studies, are urgently needed to quantify exposure levels and assess biological responses. From a regulatory perspective, the lack of pharmacopeial assays tailored to SLS dosage forms prevents standardized quality control. For example, no validated tests currently exist to measure MNP release during drug dissolution, or to predict powder sinterability under pharmaceutical conditions. Developing such assays, alongside predictive analytical tools (e.g., thermogravimetric analysis combined with emission monitoring), will be crucial for de-risking the technology. To enable safe clinical translation, priority actions include: 1. Comprehensive toxicological studies on SLS-processed polymers, with emphasis on VOCs, degradation products, and MNP formation. 2. In vivo pharmacokinetic and toxicodynamic investigations to determine the absorption, distribution, metabolism, and excretion (ADME) of polymer-derived particles. 3. Occupational exposure studies quantifying airborne emissions across powder handling, printing, and post-processing, linked to validated safety protocols. 4. Analytical method development for real-time monitoring of polymer degradation and MNP release during sintering and drug dissolution. 5. 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MDPI AG August 1, 2021. https://doi.org/10.3390/pharmaceutics13081212. Information & Authors Information Version history V1 Version 1 18 October 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords additive manufacturing (am) nanoparticles pharmaceutical powders selective laser sintering (sls) toxicity Authors Affiliations Klara Maria Dorożyńska 0009-0000-0884-1603 Uniwersytet Komisji Edukacji Narodowej w Krakowie View all articles by this author Ewelina Baran Uniwersytet Komisji Edukacji Narodowej w Krakowie View all articles by this author Przemysław Dorożyński 0000-0001-6835-2916 [email protected] Uniwersytet Jagiellonski w Krakowie Collegium Medicum View all articles by this author Grzegorz Formicki Uniwersytet Komisji Edukacji Narodowej w Krakowie View all articles by this author Piotr Kulinowski 0000-0002-8656-0310 Uniwersytet Komisji Edukacji Narodowej w Krakowie View all articles by this author Metrics & Citations Metrics Article Usage 238 views 143 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Klara Maria Dorożyńska, Ewelina Baran, Przemysław Dorożyński, et al. A New Approach to Manufacturing Oral Drug Delivery Systems via Selective Laser Sintering with Water-Insoluble Biocompatible Thermoplastic Polymers: Gaps, Risks, Challenges, and Future Directions. Authorea . 18 October 2025. DOI: https://doi.org/10.22541/au.176075115.59351562/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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