Three-Dimensional Printing for Cancer Applications: History
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Subjects: Oncology
Contributor:
Ruixiu Li

As a variety of novel technologies, 3D printing has been considerably applied in the field of health care, including cancer treatment. With its fast prototyping nature, 3D printing could transform basic oncology discoveries to clinical use quickly, speed up and even revolutionise the whole drug discovery and development process.

  • 3D printing
  • cancer
  • personalisation
  • dosage form
  • 3D bioprinting
  • medical device

1. Introduction

Cancer remains one of the major public health issues worldwide, with 18.1 million new cases and 9.6 million deaths globally in 2018, and an increase of 70% was predicted in the next 2 decades [1]. The literature revealed that the average efficacy rate of a cancer drug was as low as 25%, suggesting that 75% of cancer patients suffered from overdoses and potential adverse reactions [2][3]. The limited success of cancer therapy is attributed to multidrug resistance, decreased permeability of the drug, extracellular enzymatic degradation, deficiency of enzymes required to activate prodrugs and dose-limiting toxicity [4][5][6].
Three-dimensional printing (3DP) has been considered an industrial revolution [7] due to the ability to deliver tailored products that serve many advantages on more than one level. First, it has been established that the “one size fits all” approach is not effective when it comes to therapy owing to the variability between patients considering factors such as age, genetics, anatomy, underlying medical conditions, allergies, etc. [8][9][10]. Second, easily creating prototypes is possible for a thorough evaluation before mass production, which is also performed on the basis of demand, thus reducing waste and avoiding unnecessary over-production [11]. Additionally, 3DP offers superior solutions for the prosthetic industry owing to the ability to simulate patient-specific complex structures with high accuracy and relative ease.

2. Clinical and Market Use of 3D-Printed Products for Cancer Treatment

There is currently no FDA approved 3D-printed drug for the treatment of cancer. Although there are various 3D-printed medical devices approved by the FDA Centre for Devices and Radiology Health (CDRH) [12], none are directly intended for cancer treatments.
However, there are implants that are approved by FDA that have the potential to repair damage caused by cancer. For instance, the SpineFab® Vertebral Body Replacement (VBR) System developed by Oxford Performance Materials, Inc. obtained FDA approval through the 510(k) pathway in July 2015 [13]. The aforementioned SpineFab® device is designed with the company’s custom polyetherketoneketone (PEKK) technology known as OXPEKK® in tandem with proprietary 3DP technology [13]. The spinal column that is affected due to the presence of a tumour can be replaced with SpineFab® device [14].
Three-dimensional printing of the tumour models enables the personalisation of cancer treatment [15]. The FDA outlines the regulatory requirement for 3DP of patient-specific structural models as it is classified as a Class II medical device [16]. Materialise NV is the first company to obtain FDA approval for its 3DP software, Materialise Mimics inPrint [16]. The software is designed to generate files for 3DP of structural models which can be used for surgical preparation [16].

2. 3D Printing of Anticancer Dosage Forms

Since the report of the first 3D-printed pill for drug delivery purposes in 1996 [17], 3DP technologies have been increasingly utilised for pharmaceutical manufacturing, landmarked by the emergence of the first FDA approved 3D-printed medicine, SPRITAM®, in August 2015. A precedence has been set for the manufacture of novel dosage forms using 3DP technologies [18]. Yet so far, there is no FDA-approved 3D-printed medicine for cancer treatment in the market; many researches have been pioneered to investigate 3D-printed anticancer dosage forms (Table 1), from the local delivery implant and oral dosage form to transdermal dosage form as discussed below.
Table 1. 3DP of anticancer dosage forms.
Types of Dosage Forms Dosage Forms APIs Diseases Types of Printer Matrixes References
Implants for local chemotherapy or thermotherapy Scaffold DOX Bone cancer FDM Chitosan, nanoclay and β-tricalcium phosphate, PCL [19]
Drug-eluting implant DOX and apo2l/trail Bone cancer SLM Ti6A14V [20]
Magnetic hyperthermia scaffold DOX Bone cancer PE Fe3O4/MBG/PCL [21]
Photothermal scaffold non Bone cancer N/A Ca-P/polydopamine [22]
Photothermal bioscaffold non Bone cancer N/A Fe-CaSiO3 [23]
Photothermal hydrogel scaffolds PDA Bone cancer Bioscaffolder Alg-PDA [24]
Nanoporous disc DOX Bone metastases secondary to prostate cancer FDM TPU [25]
Tablet Progesterone Breast, ovarian, uterus and prostate cancers SLS PCL [26]
Bullet-shaped implant Cytoxan N/A FDM PLA [27]
Magnetically actuated implant Methylene blue (MB), Docetaxel (DTX) Prostate cancer N/A ABS [28]
Magnetically controlled implant TNF-related apoptosis-inducing ligand (TRAIL) and DOX N/A Bioprinter graphene oxide and PCL composite [29]
Scaffold DOX and Cisplatin Breast cancer E-jet PLGA [30]
Scaffold 5-FU and NVP-BEZ235 Breast cancer E-jet PLGA [30]
Spherical implant DOX, ifosfamide, methotrexate, Cisplatin (CDDP) Osteosarcoma SLA PLLA [31]
Patch 5-FU Pancreatic cancer PE, MHDS PLGA, PCL [32]
Tablet Fluorouracil Cartilage cancer SLS PCL [33]
Drug delivery implant patent N/A Mouth/anal/cervical/vaginal cancer N/A N/A [34]
Nanogel discs Paclitaxel, rapamycin Ovarian cancer FDM Poloxamer 407 [35]
Mesh Temozolomide (TMZ) Glioblastoma (GBM) Bioprinter PLGA [36]
Brachytherapy device Vaginal template for brachytherapy N/A Cervical cancer Multi-jet Printing N/A [37]
Superficial brachytherapy applicator Radioisotopes of yttrium-90 Skin cancer SLA PLA [38]
Brachytherapy applicator Gafchromic ebt3 film Gynaecologic cancer FDM PLA [39]
Implants for local Immunotherapy Nanogel DNA nanocomplex Glioblastoma SLA Gelatin Methacrylamide [40]
Transdermal Dosage forms Anticancer agent coated metal microneedle 5-fluorouracil, CUR, cisplatin Skin cancer MJ Metal [41]
Microneedle Decarbazine Skin cancer SLA Propylene fumarate (PPF)/diethyl fumarate (DEF) [42]
Microneedle Cisplatin Skin cancer SLA, inkjet printer Soluplus® [43]
Oral dosage forms Tablet 5-fluorouracil Colorectal cancer DOP Caso4, Soluplus® [44]
Not stated Microparticles Paclitaxel (PTX) Cervical Cancer Piezoelectric inkjet printer PLGA [45]
Abbreviations: APIs: active pharmaceutical ingredients, Ca-P: calcium phosphate, CUR: curcumin, DOX: Doxorubicin, 5-FU: Fluorouracil, FDM: fused deposition modelling, SLM: selective laser melting; PDA: poly dopamine, PE: pneumatic extrusion, SLS: selective laser sintering, MHDS: multi-head deposition system, SLA: stereolithographic, MJ: material jetting, DOP: digital offset press technology. PTX: paclitaxel, PLGA: poly (lactic-co-glycolic acid), PLA: polylactic acid, PCL: polycaprolactone, PLLA: poly (l-lactic acid), ABS: acrylonitrile butadiene styrene, TNF: Tumour necrosis factor, TPU: thermoplastic. Polyurethane, ALG-PDA: sodium alginate/poly dopamine, MBG: mesoporous bioactive glass, NVP-BEZ235: dactolisib. E-jet: electrohydrodynamic jet, N/A: not applicable.

4. 3D Printing of Implantable Drug Delivery Devices

4.1. 3D Printing of Local Chemotherapy or Thermotherapy Implants

Three-dimension-printed implants have been widely applied in the field of bone fracture, especially fracture caused by original bone cancer or secondary cancer metastasised from other body sites [2]. Chen et al. formulated a 3D-printed tissue engineering scaffold, which not only offered mechanical support for the repair of bone defects caused by bone tumours but also performed local sustained drug release to eliminate residual cancer cells [19].

In addition to stiff implants for bone cancer, implants were also produced with high flexibility for delicate internal organ drug delivery and wound-care applications [46]. For example, flexible patches have been fabricated to treat pancreatic cancer, and they have demonstrated good anticancer effectiveness and biodegradability in both in vitro and in vivo tests [32]. In addition to this, 3D-printed hydrogels are considered a promising dosage form for promoting cell proliferation and cell differentiation, offering physical support, drug-delivering and aiding cell regulating factors. Anticancer drug-loaded hydrogels with a solid disc shape made by extrusion-based printing are able to swell up by two-fold in water within 1 h and provide biphasic drug release for 24 h [35]. Another implantable hydrogel-based mesh loaded with temozolomide-release microparticles was formulated to prevent the recurrence of glioblastoma after resection surgery [36].

4.2. 3D Printing of Brachytherapy Devices

Three-dimension-printed brachytherapy applicators, compared to conventional applicators, have been demonstrated to provide personalised radiation exposure for targeted coverage while minimising unwanted exposure to avoid medical complications [46]. Reports of 3D-printed brachytherapy devices have increased significantly in the last decade. Kim et al. have demonstrated the use of customised applicators with good dose distribution and fixation for gynaecological cancer patients after surgery [39].

4.3. 3D Printing of Local Immunotherapy Implant

Although the application of 3DP for cancer immunotherapy remains vacant, 3DP has possible applications in the field of cancer immunotherapy [47]. A 3D-printed nanogel implant releasing DNA nanocomplex was developed to eradicate residual glioblastoma cells post-surgery [40]. The implant was tested in a 3D-printed subcutaneous glioblastoma xenograft which significantly delayed the recurrence of glioblastoma. This study demonstrated the possibility of developing local gene therapy devices using 3DP technology. In the near future, 3DP could produce an artificial tertiary lymphoid which could be implanted to provide specialised immune cells for individual patients [47].

5. 3D Printing of Oral Solid Dosage Forms

With the combination of varying parameters such as printing ink compositions, tablet shapes, infill densities, many 3D-printed solid dosage forms have been produced with a variety of release kinetics, including immediate, sustained or delayed-release. These versatile release profiles made possible by 3DP provide many advantages over tablets made by traditional manufacturing, such as rapid prototyping and optimisation, improved bioavailability, better personalisation, ease of swallowing and multi-functions [46]. For instance, the first FDA-approved 3D-printed oral tablet, Spritam, which is of high porosity and dissolve within 11 sec, is aimed to resolve the difficulty in swallowing [48]. Recently, researchers have produced personalised oral tablets containing 5-FU using Drop-On-Powder 3DP technology. This tablet can be loaded with a personalised unit dose of 5-FU in high accuracy and shape fidelity [44].

6. 3D Printing of Transdermal Dosage Forms

Transdermal drug delivery is a great alternative to oral drug delivery. Drug delivery through the skin has advantages such as avoiding the liver’s first-pass metabolism, reducing pill burden and achieving good patient compliance [46]. It was estimated that each year, there are more than 1 billion transdermal patches produced globally [46]. Three-dimensional printing, as a technology manufacturing product with precise and versatile shape, enables the design and printing of transdermal patches that perfectly contour human anatomy, such as the nose [49][50]. Transdermal microneedles (MNs) have attracted much attention in recent years for their ability to create superficial pores in a painless manner on the skin and deliver small molecule drugs or big molecules such as proteins [46].

7. 3D Bioprinting of Cancer Cell Models

7.1. 2D Model vs. Animal Model vs. 3D Model vs. 3D-Bioprinted Model

Two-dimensional models have been conventionally used for cancer research due to their affordability and simplicity [51], and they have contributed to numerous drug discoveries and developments. However, the majority of researches does not directly translate into clinical use. This is attributed to the fact that 2D cell culture does not recapitulate the in vivo tumour microenvironment of humans (Table 2) [51][52]. On the contrary, animal models are expensive, and species difference [51] has led to a discrepancy in gene expression, protein expression and soluble factors (cytokines, growth factor, etc.), which are important to study the cancer progression. Three-dimensional cell culture models have been developed to overcome the issues but bring about longer culture time, unsatisfactory reproducibility and higher cost [52]. Bioprinting utilises the 3DP technology to embed viable cells, biomaterials and growth factors by layers onto a scaffold to construct a 3D bio-printed model that closely resembles the actual tissue or organ [53]. Three-dimensional bio-printed cell models have been developed to mitigate this problem, and this technology benefits from lowering the cost in tandem with increasing the flexibility and complexity of structural design [54].
Table 2. Advantages and disadvantages of 3D-bioprinted cancer models compared to other models.
Models Advantages Disadvantages References
2D culture
  • Good reproducibility
  • Low cost
  • Easy to culture
  • Lack of cell–cell and cell–extracellular interaction
  • Fails to mimic in vivo tumour microenvironment
  • Loss of various phenotypes
 [51][52]
Animal (mouse) model
  • Short lifespan
  • Less genetic variations
  • Plenty of genetic information
  • Expensive
  • Homozygosity
  • Unreliable predictions for drug safety and efficacy
  • Different responses to certain gene expression
  • Different organ systems
  • Ethical issues
 [17][55]
3D cell culture model
  • Presence of cell–cell and cell–extracellular interactions
  • Mimics in vivo tumour microenvironment
  • Various phenotypes are maintained
  • In vivo gene expressions are maintained
  • Long culture time
  • Can have bad reproducibility
  • More expensive than 2D cultures
 [52]
3D bio-printed cell model
  • Low cost
  • Able to fabricate complex structures
  • Presence of cell–cell and cell–extracellular interactions
  • Better in mimicking in vivo tumour microenvironment
  • Limited choice of materials is important depending on type of 3D printer
  • Low resolution for certain types of 3D printer
  • Low printing speed
 [52][56]

7.2. 3D Bioprinters

Numerous bioprinters are available on the market, while the rest only develop bio-printed products based on their bioprinters. One notable mention is the first commercial bioprinter, Organovo’s NovoGen MMX™ bioprinter, which is used to construct a human breast cancer model with a detailed in vivo microenvironment and provides a better insight into anticancer drug response [57]. However, Organovo does not sell its bioprinter, but rather it grants access to its technology through a partnership [58].
Another notable mention is CELLINK, the first bioink company in the world. The company also developed the world’s novel universal bioink that can be used in all 3D bioprinting systems regardless of cell types [59]. The company has a wide range of commercial bioprinters in addition to bioinks, and it has gained support from several industry leaders and bodies, including the Food and Drug Administration (FDA), Johnson & Johnson, Merck, Novartis, Roche, etc. [59].
Recently, 3D bioprinters started to gain attention for their application in hospitals globally. For example, Rastrum is a bioprinter that is developed by Inventia Life Science, which is adopted by Peter MacCallum Cancer Centre in Melbourne, Australia, and it opens up the possibility to print tumour cells of the patient to be tested in the laboratories in order to tailor drug treatment for different patients [60].

8. 3D Bioprinting of Cancer Cell Model

8.1. Angiogenesis Model

Three-dimensional bioprinting of the cancer cell model can include the incorporation of vessels, which is previously unable to achieve with other conventional cancer cell models [61]. Such progress enables a more detailed investigation of the effects of drug delivery into cancerous tissues [62]. Three-dimension-printed leaky vessel models can also be used to test the delivery of an anticancer agent to the tumour as the vasculature surrounding tumour cells is well fenestrated due to uncontrolled cell growth. This enables adjustment of the particle size and dosage of drugs to deliver the active compound more efficiently to the target site, which reduces side effects and toxicity [63].

8.2. Tumour Microenvironment

Advances in 3DP allow spatio-temporal control over cell–cell interactions, cell–matrix interactions and tumour–stromal cells distribution, hence enabling the creation of 3D tumour models that better mimic the exact in vivo tumour microenvironment and its heterogeneity [56]. This facilitates the study of disease progression and drug screening [64], which results in earlier diagnosis and better cancer treatment [63]. For example, studies have shown that capturing the tumour–stromal cells interaction is particularly important as such interaction plays a major role in drug chemoresistance [65]. Additionally, 3D-printed models with a better in vivo tumour microenvironment may mitigate the risks of failure and enables the identification of issue at an earlier stage of drug research and development [66].

8.3. Metastasis

A novel approach utilising 3DP technology (stereolithography) has been reported by Zhu et al. to develop matrices with various structural shapes to study bone metastasis due to breast cancer [15]. Two breast cancer cell types, MDA-MB-231 and MCF-7, were seeded onto the 3D-printed PEG/PEG-DA hydrogel bone matrix [15]. Hydroxyapatite (HA) nanoparticles were also included for the first time into a 3D scaffold to better mimic the bone matrix [15]. Mesenchymal stem cells (MSC) are also cultured together with MDA-MB-231 [15]. This study has shown that both breast cancer cell types show metastatic properties, with MDA-MB-231 exhibiting greater metastatic potential [15]. MSC was demonstrated to affect disease progression and alters cellular behaviour, causing more spheroidal cell formation [15].

8.4. Tumour Spheroids

Three-dimensional printing is one of the ways to create tumour spheroids, which provide advantages such as integration with imaging and biochemical assays [67]. Swaminathan et al. demonstrate the possibility to construct an entire 3D breast spheroid directly via bioprinting apart from bioprinting the individual breast cancer cells [68]. It shows for the first time that the former method facilitates the faster construction of functional tumour models while retaining the viability and structure of breast epithelial cells in different bioinks. When bioprinted in a co-culture system consisting of breast epithelial cells and endothelial cells, it can perform nearly instantaneous drug screening and other functional tests [68].

8.5. Organs-On-Chips: Microfluidics System

Organs-on-chips are designed to mimic actual human organ functions by fabricating cells along with chambers and channels into a microfluidic device [69]. Three-dimensional printing is seen as an automated, efficient and cost-efficient method to produce organs-on-chips [70]. It allows the fabrication of complex channels, tissues and heterogenous structures with greater heterogeneity that closely resembles the human physiological organ functions [70]; thus, it may serve as a drug screening platform [69].

8.6. 3D Bioprinting for Anticancer Drug Development and Therapeutic Screening

Cancer drug development poses a challenging task as only 5% of the drugs successfully transition into the market [71] and costs approximately 800 million USD [72]. This might be attributed to the fact that 2D cultures and animal models do not recapitulate the in vivo tumour microenvironment, unlike the 3D-printed cancer models [2], in which the latter also display greater drug resistance [73]. In recent years, there has been a surge in researches using 3DP technology for drug development. For instance, Chen et al. developed a novel 3D-printed microfluidic system that is capable of combining various cancer drugs and potentially increases the effectiveness of cancer treatment [54].

9. The Limitation of 3D-Bioprinted Cancer Models

One challenge is the inconsistency in drug responses from different 3D printing methods [48], which is further hindered by the limited choices of bioinks and biomaterials along with diverse bioprinters specifications [58]. This proves that a more streamlined drug screening result and bioprinting process are left to be desired [48][74]. The selection of appropriate bioinks is limited, but it is extremely important in bioprinting. Aspects of bioinks such as transparency, biocompatibility, viscosity, photo-curability and crosslink ability must all be considered based on the type of bioprinters [57][74][75]. The resolution, scalability, accuracy, printing speed and reproducibility of 3D bioprinters remains a challenge, where there are no current bioprinters that excel in all aspects. Currently, the majority of the 3D bio-printed models are scaled-down; thus, bioprinting an actual size tumour model is a challenge to tackle in the future [57][74]. Although there are 3D models that are bioprinted with vasculature, tumour microenvironment or metastatic progression, it still lacks a 3D-bioprinted model that is completely incorporated with every criterion that enables the detailed cancer research.

10. 3D Printing of Nonbiological Medical Devices

10.1. 3D-Printed Models for Training and Planning of Cancer-Related Procedures

The need for models for effective training has been provided by 3DP models representing different human anatomies and malignancies. Models could be created based on patients’ images, thus demonstrating individualised models that also act as a useful tool in patient counselling in addition to training and planning purposes [76][77]. Giovanni et al. [78] displayed 3D-printed models revealed by the literature for different purposes in urology, namely, kidney, prostate, ureter, adrenal gland, iliac vessels and bladder models. 

10.2. 3D Printing of Prosthetics after Tumour Surgery

Head and neck cancer surgery involve the removal of a significant portion of facial structures, rendering the patient deformed with loss of partial or complete function of buccofacial features, which requires reconstructive surgery [79]. Exact 3D models featuring the patient’s anatomy improves preoperative planning, intraoperative navigation and shortens the duration of surgery. Traditionally, bone grafts are used; however, they are not optimal due to limited availability, risk of wound infection and the possibility of resorption [80]. A research group in Brazil reconstructed a patient’s face, who had lost her eye and part of her jaw as a result of cancer, using 3DP. Images were simply taken by a smartphone and utilised to create protheses matching the patient’s facial features. The process was reported to be fast (12 h), cost-effective (silicon, resin and synthetic fibres) and less invasive (sculptures from manual facial imprints were replaced by digital facial impressions) [81][82].

10.3. Limitations of 3D-Printed Nonbiological Medical Devices

Although 3DP has proved to be advantageous in many aspects, it has its flaws. Three-dimension-printed models that exactly resemble human tissues and organs do not exist to date [83]. Human organs and vasculature are more flexible and softer than some of the printing materials used to fabricate the 3D models. In a kidney model created for adrenalectomy training for neuroblastoma, vessels and tumours were hard to excise due to the hardness of the printing material; also, fibrous adhesions associated with preoperative chemotherapy were not featured [84].
As 3DP is considerably a modern technique, there are no unified imaging protocols, printing materials, printers and software used, which results in different outcomes [85], so tumour size or extent of invasion might differ in reality.
In addition, time is of the essence in cancer treatment to prevent metastasis and further tumour growth, fast surgical intervention and thus planning is required, which could be problematic as the production of a model takes time.
Besides, the cost of the technology is variable and depends on several factors such as the quantity, printing materials and type of printer. 

11. Challenges and Future Orientations

There are technical and regulatory challenges and limitations as 3DP technology is still relatively new in oncological applications. The material used must be biocompatible to meet the effectiveness and safety requirements of human usage and consumption [46]. Not all printable materials are biocompatible; even though the large molecular weight polymers are compatible, the risk of monomers leaching still exists, and the heating or laser sintering printing process might cause drug degradation, which brings great safety concerns [86]. Although 3DP can be performed in an aseptic environment, sterilisation is often required for the final product. However, many 3DP materials, such as polymers, have limited choices of sterilization, and the stability of drugs under heat and light should also be considered [46]. These safety concerns have hindered regulatory approval and lead to a low clinical trial rate of 3D-printed medicine. Traditional clinical trials often require a certain number of patients, varying from 20 to 3000 according to the phase of the clinical trial. However, because many 3D-printed products are tailored for individual patients, the difficulty of meeting the requirement of the FDA via the traditional approval route has impeded the introduction of 3D-printed pharmaceutics to the market [87].
The potential of 3DP for cancer applications remains to be exploited. Three-dimensional printing could bring revolution to traditional pharmaceutical industries and current medical systems by its potential to produce a biocompatible and functioning product such as 3D-printed personal organs, cancer and surgical models and customised multifunctional medicine, which is promising in terms of reducing R&D cost and duration, providing quick feedback from individual patients and achieving the ultimate goal of personalisation.

This entry is adapted from the peer-reviewed paper 10.3390/ph14080787

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