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3D Printing Technologies in Personalized Medicine and Nanomedicines

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3D printing technologies have made significant advancements in the fields of personalized medicine, nanomedicines, and biopharmaceuticals, offering innovative solutions for drug delivery, tissue engineering, and the production of customized medical devices.

3D printing technologies in medicine allow for the customization of treatments to meet individual patient needs. Several 3D printing methods are employed, including nozzle-based extrusion, laser-writing systems, and powder binder jetting. These techniques have diverse applications, including solid and semi-solid medicines, medical devices, and locally applied treatments.

For solid dosage forms, 3D printing can combine multiple drugs in a single form, improving patient compliance, ease of swallowing, and control over drug release. It can also create new medicines when no suitable dosage form exists. Additionally, sustained-release implants and devices are used in joint replacements, prostheses, and cardiovascular therapies. Locally applied medicines like wound dressings, microneedles, and medicated contact lenses can also be produced using 3D printing.

Selecting the appropriate 3D printing technique and developing pharmaceutical inks with the required properties are key challenges. The integration of biopharmaceuticals and nanotechnology with 3D printing, often referred to as "nanoprinting," holds promise for personalized nanomedicines in the future. Continuous manufacturing using 3D-printed microfluidic chips may further enhance the translation of these innovations into clinical practice.

Here's an overview of how 3D printing is impacting these areas:

Personalized Medicine

Personalized medicine tailors treatments based on individuals' genotypes, lifestyles, and medical data. It aims to improve treatment effectiveness, reduce healthcare costs, and prevent diseases. Various terms like precision medicine and genomic medicine describe the same concept 3D printing is a powerful tool for creating custom medicines and medical devices. It can produce tablets, metallic prostheses, and nanomedicines tailored to patient needs.

3D Printing of Medicines

3D printing, a process of layering 2D sheets to create 3D objects, is gaining popularity due to its versatility and cost-effectiveness. It offers precise customization of pharmacological therapies to suit individual patient needs.

Applications in Healthcare

3D printing has diverse applications, including printing medicines (topical, oral, and parenteral forms), personalized implants, and prostheses. It also explores 4D printing, where implants can change shape over time within the patient's body. In tissue engineering, 3D printing creates scaffolds for 3D cell cultures and organ-on-a-chip models that closely mimic human tissues, reducing the need for animal testing. Microfluidic chips produced using 3D printing support cell growth and nanomedicine production.

Technical Considerations for 3D Printing Medicines

To 3D print medicines, design the structure using CAD software or obtain it from a 3D scanner. Slice the design into layers, generating a g-code file for the printer. Specific printing techniques require suitable materials. Fused Deposition Modeling (FDM) requires a flexible filament with the drug. Stereolithography (SLA) uses a photopolymerizable resin mixed with the active ingredient exposed to UV light. Other techniques, like semisolid extrusion (SSE), employ semiviscous mixtures of active ingredients and excipients in prefilled syringes deposited on the printer platform. Proper drug stability throughout printing is crucial for solid dosage forms.

Challenges to Bringing 3D Printing Technology to Clinical Practice

One major challenge is the time it takes to 3D print medicines, ranging from 7 seconds to 15 minutes, which is much slower than traditional tablet presses capable of producing millions of tablets per hour.

Cost is another hurdle, as meeting stringent quality standards raises the price of 3D-printed medicines. This includes implementing effective decontamination protocols to prevent cross-contamination. Currently, only one GMP-compliant 3D printer for medicines, M3DIMAKER, is available at a cost of approximately EUR 80,000. FabRx has addressed cross-contamination concerns by incorporating printing within blister packaging.

Selecting pharmaceutical-grade excipients with clear audit trails limits manufacturing options. Regulatory and ethical handling of these products is still evolving, and standard pharmacopoeia tests like disintegration may be challenging for 3D-printed solid dosage forms.

Training healthcare professionals in 3D printing is crucial, despite the increasing availability of 3D printers in households. Ensuring quality standards requires expertise and knowledge, necessitating suitable training at points-of-care for successful clinical implementation of this technology.

Differences Between Conventional Drug Manufacturing and 3D Printing

Conventional Drug Manufacturing

Involves techniques like direct compression, wet granulation, and dry granulation. Solid dosage forms like tablets undergo a complex manufacturing process. Granulation processes may be required to improve powder compression. Sequential steps include mixing, granulating, and tableting, often with additional coating.

3D Printing

Requires a single step after preparing the pharmaceutical ink. The choice of 3D printing technique depends on the type of medicine desired. Main 3D printing categories are nozzle-based deposition and laser-writing systems. Nozzle-based deposition includes FDM, DPE, SSE, and PAM.Laser-based writing techniques include SLA and SLS.

3D Printing with FDM:

  • Involves creating filaments with APIs and excipients for printing.
  • Filaments are produced via a hot extrusion process.
  • Control of extrusion temperature is crucial, especially for thermolabile drugs.
  • Printing parameters like layer height and printing speed are adjusted.
  • Common excipients include PLA, PVA, Soluplus, EC, and more.
  • Offers advantages like improved drug solubility and microbiological control.

Alternative Techniques (DPE and SSE):

  • Overcome FDM challenges and are suitable for clinical settings.
  • DPE and SSE avoid filament production.
  • Powder mixture is heated before printing to ensure even distribution.
  • Used for creating personalized medicines, e.g., pediatric formulations.

Pharmaceutical 3D Printing with PAM:

  • Suitable for tissue engineering and personalized medicines.
  • Utilizes bioinks containing cells, polymers, and hydrogel precursors.
  • Bioinks must balance viscosity for structural integrity and cell growth.
  • Solvents may be needed for solid dosage forms, requiring post-printing steps.
  • Common excipients include Carbopol, PEG, HPC, HPMC, and PVP.

Laser-Based Writing Techniques (SLA and SLS):

  • SLA offers high resolution but requires UV-curing of resin with API.
  • SLS uses a powdered mixture fused by laser light.
  • No need for support structures during printing.
  • Parameters like laser power and exposure time must be carefully adjusted.
  • Consider API characteristics and product profile when choosing a 3D printing method.
  • SLA has precision applications like microfluidic chips and dentistry.

Conclusion
3D printing revolutionizes pharmaceutical manufacturing by simplifying processes, enhancing drug properties, and offering customized solutions for various medical needs. Each 3D printing technique has its advantages and challenges, making it essential to choose the right one based on drug characteristics and desired product profile.

Implementation of 3D Printing in Personalized Solid, Topical, Parenteral Dosage Forms and Medical Devices

Solid Dosage Forms
Powder binder jetting is an industrial 3D printing tech used by Aprecia labs for Spritam, a 1000 mg oral dispersible tablet. No heat required; it relies on a powder bed and liquid binder. Tablets are directly printed, minimizing waste and disintegrate rapidly. Nozzle-based extrusion and laser-writing systems are more common in research. Polypills, combining multiple drugs in one tablet, are made using FDM technology. Other techniques include PAM and SSE, but solvent removal is a challenge. 3D printing enables diverse drug combinations and modified release profiles. Capsule shells, oral dispersible films, and data markings can also be 3D printed.

Medical Devices
3D printing used to create personalized prostheses and medical devices. Ongoing clinical trials explore 3D-printed oral medications for various conditions. Aprecia labs and Triastek invest in 3D printing for solid dosage forms. More focus on personalized prostheses and medical devices in clinical trials.

3D-Printed Medical Devices

3D printing has emerged as a promising technology for manufacturing medical devices, with material choice being crucial. Metallic biomaterials like iron, magnesium, zinc, titanium, cobalt, and stainless steel are gaining attention. Iron, with alloys like Mn and Pd, is used for temporary cardiovascular stents due to its strength and biodegradability. Stainless steel offers good mechanical properties but may lead to issues like corrosion and inflammation. Titanium, highly biocompatible, is used in orthopedics and dentistry. Magnesium, lightweight but quick to degrade, finds application in orthopedic screws. Zinc supports bone tissue growth and is used for various devices. Cobalt alloys excel in magnetic properties and wear resistance, serving in pacemakers, implants, and stents in medicine. Material selection depends on specific device requirements.

3D-Printed Implants

  • Biodegradable polymers like PLA, PGA, PVA, PCL, and their copolymers allow for long-lasting implants.
  • FDM 3D printing successfully delivers various APIs, including hormones and antimicrobials.
  • Implants like vaginal rings and breast cancer scaffolds exhibit prolonged drug release.
  • Biodegradable stents can be coated with antimicrobials and anti-inflammatory drugs.
  • 4D printing introduces dynamic structures that change in response to stimuli, enabling smart drug delivery.

3D Printing on Skin and Eye Surface

  • 3D printing has applications in wound dressings and microneedles on the skin.
  • PAM technology is suitable for wound-healing dressings with promising bioink development.
  • Chitosan-based hydrogels with lidocaine maintain a moist, pain-free wound healing environment.
  • Antibacterial wound dressings loaded with metals are fabricated using hot-melt extrusion.
  • High-resolution SLA is used for 3D-printed microneedles for insulin delivery and skin tumor treatment.

3D Printing in Contact Lenses

  • 3D printing in contact lenses requires transparency, sterility, flexibility, and oxygen permeability.
  • Digital light processing and dental resins are used, followed by post-printing processes.
  • Medicated contact lenses for glaucoma use FDM and biocompatible polymers with controlled drug release.

In summary, 3D printing has diverse applications in creating implants, drug delivery systems, wound dressings, microneedles, and even contact lenses, offering innovative solutions in personalized medicine and healthcare.

3D Printing in Personalized Biopharmaceuticals

The application of 3D printing in biopharmaceuticals is gaining traction, offering innovative possibilities in precision medicine. While most 3D printing research has focused on small molecules, the burgeoning biopharmaceutical market is exploring new avenues, particularly in personalized organ-on-chip manufacturing. This involves peptides and proteins, with applications in tissue engineering, such as cartilage and bone regeneration. Combining biopharmaceuticals with cell-based scaffolds has demonstrated enhanced tissue growth. Examples include bilayered porous scaffolds for cartilage and subchondral regeneration and PLA scaffolds promoting osteogenesis.

Hydrogels play a crucial role, eliminating the need for heating during printing, but their rheological properties pose challenges. Hence, a common approach is combining PAM with FDM printing to create mechanically robust scaffolds using biocompatible polymers. Peptide hydrogel design involves optimizing the amphiphilic balance of the backbone sequence to enable physical gelation driven by interactions like H-bonding, charge–charge interactions, and π–π stacking.

Innovations also extend to 3D-printed solid dosage forms with biopharmaceuticals. For instance, tablets with specific release profiles have been developed, and polymeric microneedle patches loaded with insulin show promise in transdermal delivery. Moreover, multiunit implants enable remote light-controlled protein drug delivery through near-infrared light-induced release, demonstrating efficacy in diabetic mouse models. These advancements highlight the potential of 3D printing in biopharmaceuticals, particularly with the resilience of peptides in material extrusion techniques.

Nanomedicine and 3D Printing

Nanomedicine utilizes nanomaterials for diagnosis, drug delivery, and regenerative medicine due to their unique properties. Inorganic and organic nanoparticles are widely used, with liposomes being common in cancer treatment. Flexible transferosomes are used for topical drug delivery, and self-nanoemulsifying systems (SNEDDS) enhance drug solubility. Polymeric nanoparticles are researched for tumor targeting.

3D printing is transforming nanomedicine manufacturing. Challenges include nanoparticle aggregation, but preprocessing techniques can improve homogeneity. 3D-printed solid dosage forms, including polyphenols and liposomes, show promise in drug delivery. Metallic implants and medical devices are also customized through 3D printing.

Scaling Up Nanomedicine Production

Conventional methods like solvent evaporation have limitations in scaling up nanomedicine production due to solvent removal challenges and lack of control over drug polymorphism. Continuous manufacturing, despite its potential, faces challenges like batch-to-batch reproducibility and stability issues.

Microfluidic devices offer precise control and automation, but traditional fabrication methods face obstacles. 3D printing overcomes these issues, allowing high-throughput nanomedicine synthesis with tunable properties. It provides an advantage over batch production.

Challenges and Future Perspectives

3D printing in personalized medicine holds vast potential but faces slow clinical translation due to complexity, regulatory issues, and cost. Standard 3D printers may not meet regulatory standards, and high-quality GMP printers are expensive. Healthcare personnel need proper training to ensure quality standards and minimize variability.

Regulatory bodies like the FDA, EMA, and PMDA should collaborate on clear guidelines for 3D-printed medicines. Progress is expected in the next decade, changing the landscape of personalized medicine.

3D Printing Technologies in Personalized Medicine and Nanomedicines
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