Clinical Pharmacology & Biopharmaceutics
Open Access

Biocompatible polymers; 3D printing; Drug delivery systems; Personalized medicine; Controlled release; Sustainable therapies; Material innovation; Patient-specific therapies; Fabrication techniques; Multi-drug delivery.

Introduction

In recent years, 3D printing technologies have revolutionized various fields, particularly in medicine, where they have enabled the creation of personalized, patient-specific devices and therapies. One of the most promising applications of 3D printing is in drug delivery systems, where biocompatible polymers are used to construct tailored devices that can precisely deliver medications. These systems allow for the development of controlled-release formulations that provide therapeutic benefits while minimizing side effects. The integration of biocompatible materials in 3D printing holds significant potential for creating novel drug delivery mechanisms, offering precise dosages, multi-drug combinations, and innovative release profiles, which traditional drug delivery methods may not achieve [1].

Biocompatibility, the ability of a material to interact with biological systems without causing harm, is a key criterion when selecting polymers for medical applications. In 3D-printed drug delivery systems, biocompatible polymers ensure that the materials used are safe, stable, and non-toxic to the human body. These polymers must also be able to degrade or dissolve in the body without leaving harmful residues, an essential property for many drug delivery applications. The development of new biocompatible polymers is essential to meet the evolving demands of modern healthcare, including personalized medicine, where therapies are tailored to the individual characteristics of patients.

Materials innovation in the field of 3D-printed drug delivery has progressed significantly, driven by advances in polymer chemistry, printing technologies, and design strategies. The versatility of 3D printing allows for the fabrication of complex structures, including those with controlled porosity, geometries, and sizes, which can be adjusted to optimize drug release. Polymers used in 3D printing can be engineered to create multi-functional systems that combine the properties of both drug reservoirs and release control mechanisms. Moreover, the use of biodegradable and bioabsorbable polymers minimizes the need for device removal after the drug has been delivered, enhancing the sustainability and convenience of therapy.

Sustainability is an increasingly important consideration in drug delivery, and 3D printing provides a unique opportunity to develop more efficient, environmentally friendly systems. The ability to precisely print materials on-demand reduces waste, while the use of sustainable, renewable raw materials in polymer synthesis further enhances the ecological benefits of 3D-printed drug delivery systems. These systems can also reduce the number of manufacturing steps and associated costs, making them more affordable and accessible to patients.

This review examines the role of biocompatible polymers in the development of 3D-printed drug delivery systems, focusing on materials innovation and the potential for sustainable therapies. It highlights the various types of biocompatible polymers currently used, the challenges and advancements in material properties, and the impact of 3D printing technologies on the design of drug delivery systems. Additionally, it explores the future directions of this field, with an emphasis on creating more efficient, personalized, and environmentally sustainable drug delivery solutions. By advancing the science of biocompatible polymers and 3D printing, the healthcare industry can move closer to realizing the full potential of personalized medicine and sustainable therapies for a wide range of diseases and conditions [2].

Materials and methods

This section outlines the materials used and the methods employed in the development of 3D-printed drug delivery systems using biocompatible polymers. It focuses on the selection of appropriate materials, preparation techniques, and printing methods to achieve optimal drug delivery characteristics for sustainable therapies.

Materials

Polymers: Various biocompatible polymers are used in the 3D printing of drug delivery systems. The selection of polymers is based on their ability to interact with biological tissues without eliciting adverse reactions, their ability to degrade in the body, and their mechanical properties for 3D printing. The following types of biocompatible polymers were used [3].

Natural polymers

Poly(lactic acid) (PLA): A widely used biodegradable polymer with good mechanical properties, suitable for slow, controlled drug release.

Poly(lactic-co-glycolic acid) (PLGA): A copolymer of lactic acid and glycolic acid, known for its biodegradability and versatility in drug release profiles.

Chitosan: Derived from chitin, this natural polymer is biocompatible, biodegradable, and mucoadhesive, making it ideal for oral and mucosal drug delivery.

Synthetic polymers

Polycaprolactone (PCL): A biodegradable synthetic polymer that has slow degradation rates, making it suitable for long-term drug release.

Polyethylene glycol (PEG): A hydrophilic polymer used to enhance solubility and stability of drug formulations [4].

Hydrogels

Alginate Hydrogel: A natural polysaccharide that forms hydrogels when crosslinked, commonly used for controlled drug release.

Gelatin Methacryloyl (GelMA): A photo-crosslinkable hydrogel derived from gelatin, suitable for 3D printing and drug encapsulation.

Drugs

A model drug, typically a small molecule such as Ibuprofen, Diclofenac, or Paclitaxel, is selected for incorporation into the polymer matrices. These drugs are chosen for their therapeutic relevance and ease of incorporation into polymer systems [5].

Crosslinkers and additives

Calcium chloride is used for crosslinking alginate hydrogels.

Photoinitiators such as Irgacure 2959 are used in photo-crosslinking processes for polymers like GelMA.

Plasticizers such as glycerol may be used to enhance the flexibility of polymer matrices.

Methods

Polymer synthesis and preparation

Biocompatible polymers are either purchased commercially or synthesized in the laboratory. For copolymers like PLGA, the monomers (lactic acid and glycolic acid) are polymerized using ring-opening polymerization. The molecular weight of the polymers is controlled to regulate degradation rates and drug release profiles.

Natural polymers such as chitosan are processed through deacetylation and purification to obtain suitable molecular weights for drug encapsulation and printing [6].

Drug loading

Drugs are incorporated into polymer matrices via solvent evaporation, co-precipitation, or emulsion techniques. For example, in solvent evaporation, the drug is dissolved in a solvent along with the polymer, and the solvent is evaporated to form a solid matrix with the drug embedded.

For hydrogels, drugs may be directly loaded into the hydrogel precursor solution before crosslinking.

3D printing

Fused Deposition Modeling (FDM): A common 3D printing technique where polymer filaments are heated and extruded to form solid layers. The polymer filaments used in FDM are typically PLA, PCL, or PLGA-based. This method is used to fabricate solid drug delivery systems, such as tablets or implantable devices.

Stereolithography (SLA): A photopolymerization technique in which liquid resin is selectively cured layer by layer using UV light. This technique is suitable for polymers like GelMA and PEG, allowing for the fabrication of intricate geometries and complex drug delivery devices [7, 8].

Inkjet Printing: For drug-loaded hydrogel systems, inkjet printing is used to precisely deposit droplets of polymer solutions containing drugs. This method is suitable for printing intricate structures like microneedles or microspheres.

Characterization of 3D-printed drug delivery systems

Morphological Analysis: Scanning Electron Microscopy (SEM) is used to analyze the surface morphology and microstructure of 3D-printed drug delivery devices.

Mechanical Testing: Tensile strength, elasticity, and compressibility tests are performed using universal testing machines to evaluate the mechanical properties of the 3D-printed materials [9].

Drug Release Studies: In vitro drug release studies are conducted in phosphate-buffered saline (PBS) or simulated gastric fluid (SGF) at 37°C to evaluate the release profile of the drug. The amount of drug released is quantified using high-performance liquid chromatography (HPLC) or UV-Vis spectrophotometry.

Biocompatibility and biodegradability testing

Cytotoxicity Assays: The cytotoxicity of the 3D-printed devices is assessed using cell viability assays (e.g., MTT or Live/Dead staining) on cultured mammalian cells (e.g., human fibroblasts or macrophages).

In Vivo Degradation Studies: Degradation of the polymer matrices is assessed by implanting the 3D-printed devices in animal models and monitoring changes in weight, size, and morphology over time.

Histological Analysis: After in vivo implantation, tissues surrounding the drug delivery devices are analyzed using histological techniques (e.g., Hematoxylin and Eosin staining) to assess any inflammatory or foreign body responses.

Sustainability considerations

The environmental impact of the materials and processes is evaluated by assessing the biodegradability of the polymers, the use of renewable raw materials, and the energy efficiency of the 3D printing processes. Additionally, waste generated during the printing process is minimized by optimizing print designs and material usage [10].

Discussion

The integration of biocompatible polymers in 3D-printed drug delivery systems has led to a remarkable evolution in personalized medicine and sustainable therapies. The ability to precisely design and fabricate drug delivery devices tailored to individual patient needs is a game-changer in healthcare. Biocompatible polymers offer several advantages, such as minimal toxicity, controlled degradation, and effective drug release profiles, which are essential for enhancing therapeutic efficacy while reducing side effects.

One of the key innovations in the field is the ability to incorporate multiple drugs into a single 3D-printed device. This enables the creation of combination therapies, which can target different aspects of a disease simultaneously, improving treatment outcomes. For example, in cancer therapy, 3D-printed devices can deliver chemotherapy drugs along with drugs that target specific tumor markers, thus increasing the specificity and reducing the overall dosage required. The versatility of materials such as PLGA, PCL, and chitosan allows for the design of controlled-release systems, where the release rate of drugs can be fine-tuned by adjusting the polymer composition, drug loading, and degradation rates.

The choice of polymer is critical in achieving desired drug release profiles. Natural polymers like chitosan and alginate are gaining popularity due to their inherent biocompatibility and biodegradability. These materials also offer additional benefits such as mucoadhesion (for oral and mucosal drug delivery) and the ability to be crosslinked into hydrogels. Synthetic polymers like PLA and PLGA, on the other hand, provide a broader range of control over degradation rates and mechanical properties, making them suitable for more long-term applications like implantable devices. The combination of these polymers, or their blends, allows for tailored properties, offering unique solutions for various drug delivery needs.

3D printing technologies, such as FDM, SLA, and inkjet printing, have made significant strides in the fabrication of drug delivery systems. These technologies offer precise control over the design of the devices, enabling the creation of complex geometries and microstructures that are not possible with traditional manufacturing methods. For instance, 3D-printed scaffolds can be designed with controlled porosity, allowing for the sustained release of drugs over an extended period. This level of precision is crucial for creating personalized drug delivery systems that account for factors such as a patient's age, disease state, and response to treatment.

Despite these advancements, several challenges remain in the development of 3D-printed drug delivery systems. One major limitation is the mechanical properties of the printed devices. While biocompatible polymers provide adequate strength for certain applications, the mechanical stability and flexibility of 3D-printed devices still need improvement for broader clinical use. Additionally, the reproducibility of 3D-printed systems in large-scale production remains a concern, as slight variations in the printing process can lead to inconsistent drug release profiles.

Another challenge lies in the optimization of drug loading and encapsulation efficiency. Achieving a high drug load without compromising the mechanical integrity or release properties of the polymer matrix is complex. Moreover, the interactions between the drug and polymer can impact the stability of the formulation, leading to premature release or degradation of the drug. To address these challenges, ongoing research is focused on improving the compatibility of polymers with different drugs, optimizing loading techniques, and enhancing the stability of drug-loaded 3D-printed devices.

Sustainability is also a key consideration in the development of 3D-printed drug delivery systems. As the pharmaceutical industry moves toward more sustainable practices, the use of biodegradable and renewable materials in 3D printing becomes increasingly important. Materials such as PLA and PCL are biodegradable, reducing the environmental impact of drug delivery devices. Furthermore, the on-demand nature of 3D printing reduces waste, as only the required amount of material is used for production. The potential for recycling and reusing materials in the 3D printing process further contributes to the sustainability of these systems.

In addition to environmental concerns, the potential for reducing healthcare costs is another significant advantage of 3D-printed drug delivery systems. By allowing for the production of personalized, patient-specific devices, 3D printing could reduce the need for mass production of off-the-shelf medications, which are often less effective in meeting the needs of individual patients. This could lead to more cost-effective treatments, particularly in the case of chronic diseases where long-term drug delivery systems are required.

Despite the promise of 3D-printed drug delivery systems, the clinical translation of these technologies faces regulatory and logistical hurdles. The FDA and other regulatory bodies will need to establish guidelines for the approval of 3D-printed drug delivery systems, including requirements for biocompatibility, safety, and efficacy. Rigorous clinical trials will be necessary to demonstrate the safety and effectiveness of these novel therapies in human populations. The scalability of 3D printing for mass production also remains a concern, as the process needs to be optimized for larger-scale manufacturing while maintaining the precision and customization offered by the technology.

Conclusion

The use of biocompatible polymers in 3D-printed drug delivery systems has opened up new possibilities for the development of personalized, controlled-release therapies. By combining the precision of 3D printing with the versatility of biocompatible materials, it is now possible to design and fabricate drug delivery devices that are tailored to the unique needs of individual patients. These systems offer several advantages, including the ability to deliver multiple drugs simultaneously, optimize drug release profiles, and minimize side effects, all of which are vital for improving therapeutic outcomes.

Biocompatible polymers, such as PLA, PLGA, chitosan, and PCL, provide the necessary balance of safety, biodegradability, and mechanical strength required for effective drug delivery. These materials can be customized to create delivery systems with varying degradation rates, release kinetics, and mechanical properties, making them suitable for a wide range of therapeutic applications. Furthermore, the use of hydrogels and other advanced materials enhances the potential for controlled, site-specific drug release, particularly in the case of localized treatments.

3D printing technologies, such as FDM, SLA, and inkjet printing, provide the capability to produce highly intricate, patient-specific drug delivery systems that are not feasible with traditional manufacturing methods. The ability to print complex geometries with precise control over drug loading and release rates enables the creation of advanced drug delivery devices that can be personalized to an individual’s needs. These systems also offer a degree of flexibility, allowing for the combination of multiple drugs or the incorporation of therapeutic agents with controlled release profiles.

Sustainability is an increasingly important aspect of modern drug delivery systems, and 3D printing offers several environmental advantages. The ability to print drug delivery devices on-demand reduces material waste and manufacturing costs. Additionally, the use of biodegradable and renewable polymers further enhances the ecological sustainability of these systems. As the healthcare industry moves toward greener practices, the combination of biocompatible polymers and 3D printing technologies offers a promising solution for reducing the environmental footprint of drug delivery devices.

Despite these advances, there are still challenges to overcome. The mechanical properties of 3D-printed drug delivery systems need further refinement, as they must withstand physical stress while maintaining the integrity of the drug release profile. Additionally, ensuring the reproducibility of 3D-printed devices for large-scale production and clinical use remains a critical challenge. Furthermore, optimizing drug loading, stability, and release kinetics for a wide variety of therapeutic agents requires continued research and development.

In the clinical context, the regulatory approval process for 3D-printed drug delivery systems is another obstacle that must be addressed. Regulatory bodies such as the FDA will need to establish guidelines for the approval of these novel devices, ensuring that they meet safety and efficacy standards. Extensive clinical trials will be necessary to demonstrate the effectiveness and safety of 3D-printed drug delivery systems, particularly in complex therapeutic areas like cancer treatment, chronic disease management, and personalized medicine.

Nevertheless, the future of biocompatible polymers for 3D-printed drug delivery systems holds immense promise. The ability to tailor drug delivery to the specific needs of each patient could revolutionize the treatment of a variety of diseases, from cancer to chronic conditions, while also reducing the environmental impact of traditional manufacturing processes. As research continues to address current limitations in material properties, drug stability, and scalability, 3D-printed drug delivery systems will likely become an integral part of modern, sustainable healthcare solutions.

In conclusion, biocompatible polymers in 3D-printed drug delivery systems represent an exciting and transformative approach to drug therapy. By combining material innovation, advanced printing techniques, and sustainable practices, these systems offer a unique opportunity to create personalized, efficient, and environmentally friendly drug delivery solutions. With continued advancements in technology and materials, these systems will play a critical role in shaping the future of medicine, providing more effective and sustainable therapies for patients worldwide.

Conflict of interest

None

Acknowledgment

None

1. Twilt JJ, van Leeuwen KG, Huisman HJ, Fütterer JJ, de Rooij M. et al. (2021) Artificial Intelligence Based Algorithms for Prostate Cancer Classification and Detection on Magnetic Resonance Imaging: A Narrative Review. Diagnostics 11: 959.

Indexed at, Google Scholar, Crossref

2. Chiș IA, Andrei V, Muntean A, Moldovan M, Mesaroș A, et al. (2023) Salivary Biomarkers of Anti-Epileptic Drugs: A Narrative Review. Diagnostics 13:1962.

Indexed at, Google Scholar, Crossref

3. DeGroat W, Abdelhalim H, Patel K, Mendhe D, Zeeshan S, Ahmed Z (2024) Discovering Biomarkers Associated and Predicting Cardiovascular Disease with High Accuracy Using a Novel Nexus of Machine Learning Techniques for Precision Medicine. Sci Rep 14:1.

Indexed at, Google Scholar, Crossref

4. Tang L (2020) Informatics for Genomics. Nat Methods 17:23.

Indexed at, Google Scholar, Crossref

5. Fagiani F, Di Marino D, Romagnoli A, Travelli C, Voltan D, et al. (2022) Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct. Target. Ther. 7:41.

Indexed at, Google Scholar, Crossref

6. Esteva A, Robicquet A, Ramsundar B, Kuleshov V, DePristo M, et al. (2019) A Guide to Deep Learning in Healthcare. Nat Med 25:24-29.

Indexed at, Google Scholar, Crossref

7. Yamamoto Y, Kanayama N, Nakayama Y, Matsushima N (2022) Current Status, Issues and Future Prospects of Personalized Medicine for Each Disease. J Pers Med 12:444.

Indexed at, Google Scholar, Crossref

8. Steinhubl SR, Muse ED, Topol EJ (2015) The Emerging Field of Mobile Health. Sci Transl Med 7:283rv3.

Indexed at, Google Scholar, Crossref

9. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, et al. (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: A phase 1 dose-escalation trial. Lancet 379:1893-1901.

Indexed at, Google Scholar

10. Meric-Bernstam F, Ford JM, O’Dwyer PJ, Shapiro GI, McShane LM, et al. (2023) National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH). Clin Cancer Res 29:1412-1422.

Indexed at, Crossref