TECH SPECIAL .....Evaluation of 3D Printing and Its Potential Impact on Biotechnology and the Chemical Sciences PART 4

Evaluation of 3D Printing and Its Potential Impact on Biotechnology and the Chemical Sciences

PART 4

Current Applications

The assortment of topics that follows is not meant to be an inclusive list on the full applications of 3D printing technology. Rather, it aims to give the reader an appreciation for the potential 3D printing has in an array of disciplines. Specifically, the topics to be discussed are the applications of rapid prototyping in biomedical engineering, pharmacokinetics/pharmacodynamics, forensic science, education, micro/macrofluidics, electronics, scaling (industry), and customizable labware.

Biological Applications

Biomedical Engineering

Tissue Scaffolding

Additive manufacturing has found widespread use as a tool to bioengineer tissue, varying in composition from bone and teeth to vascular and organ scaffolding. Major concerns when introducing a foreign scaffold to the body are the ability of the material to be absorbed by the body (bioresorption) and whether or not it will be rejected by the body (biocompatibility). For these reasons, scaffolds are traditionally comprised of tissue taken from the individual in need (autogenous tissue). However, in some cases the required scaffold area is large enough that autogenous tissue sampling is not feasible for the patient. The ability to customize a 3D printed scaffold for tissue regeneration allows for individualized treatment while avoiding the need to sample from the patient’s own tissue for scaffold formation. In this respect, 3D printing has become an attractive avenue for the development of biocompatible materials that are resorbable.(-68, 69) Electrospinning is one of several fabrication methods that have been conventionally used for bone scaffold materials and is capable of fabricating bone replicate fibers that are submicrometer to nanometer in diameter. This fabrication technique relies on a high voltage power supply to electrospray a polymer feed solution containing nanoparticles of bone substitute from a nozzle onto a conductive rotating drum. Limitations with this method include the utilization of a high voltage (often >20 kV) as well as lack of control over scaffold geometry and porosity as is encountered with other traditional methods.

Autogeneous bone is ideal for bone graphs, as it allows for new bone growth at the implantation site due to already present growth factors. The risk of infection, often seen with foreign implants, is lowered in patients with autogenous grafts. Many bone replicate materials are made from calcium phosphate ceramics (tricalcium phosphate (TCP, Ca₃(PO₄)₂), hydroxyapatite (HA, Ca₁₀(PO₄)₆(OH)₂), calcium phosphate cements (CPC), monetite (CaHPO₄), or brushite (CaHPO₄·2H₂O)), as these are comparable to the mineral components of bone. This is not an exclusive list, however, as new combinations of materials are being tested for increased bioresorption and biocompatibility, such as a β-TCP and bioactive glass mixture. These materials are made into 3D scaffolds by selective laser sintering, inkjet-based printing, or printing the powdered form of the chosen material with an organic binder to form a ceramic 3D scaffold. The porosity of the implant becomes important as implant adhesion to bone occurs through bone ingrowth into the pores of the prosthetic and it facilitates biodegradability of the scaffold due to reduced material presence. Ideal porosity and pore size of the 3D printed scaffold to encourage bone ingrowth have been reported as 30–70% and 500–1000 μm, respectively. However, micro to macroscopic pore sizes ranging from less than 20 μm to 0.5 mm have been reported. Each of the bone replicate materials have a different pore size and achievable porosity, and the choice of bone scaffold material depends largely on the purpose of the graft, as the materials used to form 3D grafts have variable resorption times. For example, monetite structures have been found to absorb faster into muscle than brushite. Many articles have outlined fabrication and in vivo and/or in vitro testing of various bone substitute materials, with 3D printed materials displaying comparable biocompatibility to commercial bone substitutes.

Soft tissues have previously been fabricated using a number of techniques including thermally induced phase separation. This technique requires a polymer mixed with a solvent to be injected into a glass mold; after several tedious steps (including 3 h in liquid nitrogen, followed by a 7 day incubation in alcohol to remove the solvent, and a day to dry) the scaffold is completed. Traditional techniques for soft tissue fabrication suffer from lengthy protocols and a lack of control with regards to scaffold porosity. Producing synthetic organs for organ transplants is plausible when utilizing 3D tissue engineering. While the technology is still far from achieving this ambitious goal, 3D printing allows for the printing of cells and hydrogels, which are hydrated polymers that provide a biodegradable structure onto which cells can adhere and grow. When using hydrogels for tissue engineering, the scaffold must be biocompatible, retain its structure, and allow for cell adherence and growth. Scaffold dimensions range from μm to mm, with a variety of materials available depending on the desired scaffold strength, porosity, and type of tissue application (soft or hard). Hydrogels are most suited for soft tissues. Ideal porosity composition of scaffolds for tissue engineering has been reported to be between 60 and 80%, with pore sizes ranging from 100 to 500 μm.(88) Reviews by Tsang and Bhatia,(89) Fedorovich et al.,(90) and Yeong et al.(71) highlight 3D tissue engineering techniques available for printing cells and tissue scaffold materials as well as the various compositions that can be selected to suit a specific application. Inkjet and direct writing are commonly used 3D printing techniques for soft tissue fabrication and offer a faster completion time than their predecessors.

Examples of hydrogel applications for tissue engineering encompass a vast array of organ and soft tissues. Incorporation of support (silicon), biological (chondrocytes), and electronic (conducting silver nanoparticles) modalities has led to the development of an anatomically correct 3D printed bionic ear capable of detecting electromagnetic frequencies produced from a stereo. The liver has proven difficult to recreate on a 3D platform due to its complex structure. There are a number of rapid prototyping techniques that lend themselves to the fabrication of bioartificial livers, each with their own advantages and disadvantages. Despite the apparent challenges, there are a variety of examples where hepatocytes were successfully integrated into a 3D printed scaffold. With the number of diseases that affect the cardiovascular system, it is appropriate to apply tissue engineering for vasculature reconstruction. This has been accomplished using a variety of rapid prototyping techniques and materials, from designs as simple as a single channel,(95) to designs that recreate the complex geometries of vascular pathways,(96) and even scaffolds based off complex collagen forms.

Surgical Preparation

3D printing has facilitated advancement in individualized patient care, allowing for development of patient specific treatment plans via the printing of patient anatomy. Having a tangible model of the patient’s anatomy that can be studied before surgery serves to better prepare physicians than relying solely on 3D images acquired by MRI or CT scans, which are viewed on a flat screen. Furthermore, having an exact replica of the anatomy allows for medical procedures to be simulated beforehand. Although still in a mostly exploratory stage, there have already been numerous cases where 3D printed models have been used to gain insight into a patient’s specific anatomy prior to performing a medical procedure. Namely, this methodology has been applied in recreating a calcified aorta with 3D printing to develop a procedure for plaque removal presurgery, using a 3D model of bone growths on a shoulder to aid in surgical organization of their removal constructing a premature infant’s airway to study aerosol drug delivery to the lungs, and simulating presurgical tumor removal from a skull and deep tissue.

Pharmacokinetics/Pharmacodynamics

Inkjet-based 3D printing has been used extensively in the fabrication of drug delivery devices, as it allows for more control of the design and fabrication of implants that can be used for direct treatment. Traditional systemic treatment of localized infections affects the intended site as well as nonafflicted tissues. In many cases, such as the treatment of bone infections, it is advantageous to have direct treatment without unnecessary widespread effects. 3D printed drug implants are fabricated via the printing of binder (a solution that is able to solubilize the chosen powder) onto a matrix powder bed, facilitating controlled drug release by providing a barrier between tissue and drug, or printing of binder onto a powder bed of drug in an additive manner, resulting in layers that are typically 200 μm thick. In this manner, a number of different drug delivery devices have been designed that allow for various drug release profiles. Additive manufacturing technology has been used to fabricate drug delivery devices that are more porous than their compression-based counterparts and can incorporate powdered drugs, allowing for faster drug release. These devices can be made in a number of complex geometries, with multiple drugs loaded throughout a device, surrounded by barrier layers that modulate drug release. Traditional compression fabricated devices are made from a homogeneous mixture of support material and drug and are restrained to a continuous and singular drug release profile. For these reasons, 3D printed drug implants offer several advantages over traditional fabrication methods and have been successfully used in animal models showing localized drug dispersion.

Forensic Science

3D printing has had a meaningful impact on medical imaging in the field of forensic science, allowing for anatomically correct recreation of bodily injuries from CT and MRI scans. For example, models of both internal and external wounds have been recreated that allow for better explanation of forensic findings, while avoiding the need to present disturbing evidence in the presence of victims’ relatives. 3D printing techniques were used to recreate skull fragments from a blunt force head injury and aid in weapon identification and determination of the mechanism of injury leading to death. A similar use of 3D printing saw the recreation of a skull after a traumatic injury to deduce the cause of injury, with results comparable to those achieved using traditional methods to isolate bone from the victim. Forensic assessment of a deformed skull from the 18th century yielded a facial reconstruction based on a 3D printed version of the skull, from which authors inferred the cause of deformation.

Education

The educational applications of 3D printing extend beyond the study of anatomically correct models of body parts in healthy and diseased states. As the technology becomes more affordable, its use in educational settings is more commonplace. Recently, a model of a polypeptide chain has been fabricated using 3D printing and is able to mimic folding into secondary structures due to incorporation of bond rotational barriers and degrees of freedom considerations. Such a model could greatly aid in students’ ability to comprehend peptide structure, and the application need not be limited to biomacromolecules. Studies have led to the conclusion that students were better able to conceptualize biomolecular structures when using 3D models, as confirmed by administering pre- and postcomprehension tests.

Bethany C. Gross, Jayda L. Erkal, Sarah Y. Lockwood, Chengpeng Chen, and Dana M. Spence

Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, Michigan 48824, United States

Anal. Chem., 2014, 86 (7), pp 3240–3253

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