Based on this year’s Cancer statistics in the United States, it is estimated that the incidence of Head and neck cancers (HNC) will reach 58,450 cases, with deaths estimated to be around 12,230¹. Most of these cases constitute oral, pharyngeal, and laryngeal squamous cell carcinoma (SCC)². The treatment and management of HNC remain the same, utilizing a combination of Radiotherapy, surgery, and chemotherapy. Despite advances in high-dose and precise radiation beams (i.e., Proton therapy and image-guide intensity-modulated radiotherapy (IG-IMRT), patients are left with a very poor quality of life due to radiation-induced oral mucositis (RIOM)³, characterized by the inflammation and ulceration of the oral cavity. In this blog, we want to introduce the benefits and challenges in using 3D-printed stents to reduce radiation-induced complications.

Role of positioning oral stents in HNC radiotherapy in mitigating RIOM:

HNC patients receiving radiotherapy will typically develop RIOM within 2-4 weeks after initiation of their treatment. They can be characterized by (1) pain, sores, or redness of the oral cavity, (2) hoarseness, (3) change of taste, (4) dry mouth, and (5) sensitive teeth. Duration of these side effects varies from 6-8 weeks to as long as two or more years, with swallowing difficulties being the most common long-term effect⁴.

‘Oral stents’ for HNC radiotherapy vary in terms of designs depending on their clinical utility. Singh et al. (2021) provide a great summary of such nuances involving stents with dose shielding, radiation carrier, and positioning/immobilization capabilities⁵. This article focuses on positioning oral stents, of which are utilized by clinicians to immobilize the patient’s teeth and tongue to achieve accurate patient positioning and prevent the irradiation of healthy tissues and thus, minimizing the effects of RIOM^{5, 6}. These devices are used by patients intraorally and are used throughout the course of the patient’s treatment and vary from simple popsicle-like devices to patient-specific designs (see Fig. 1).

Manual fabrication vs. Digital 3D-printing

Patient-specific positioning stents commonly used in the clinic are often fabricated with an acrylic resin due to its biocompatibility, durability, and free-forming capabilities⁷. The manual fabrication workflow, which remains the standard of care for HNC radiotherapy, involves the acquisition of the patient’s dental impression, followed by creating a stone model and a wax pattern for modeling the acrylic stent. Often, these stent models undergo further verification and modification to ensure that the final stent model received by the patient fits correctly. Here, we are looking at an estimated 3-4 days’ worth of effort for a single stent device, involving labor-intensive processes to fabricate the final acrylic stent, and numerous patient visits and long appointments to manually acquire stone models, perform stent verifications, and modifications.

Computer-aided design (CAD) and 3D printing’s customization capabilities allow for the fabrication of complex structures and the streamlined production of customizable stents tailored to patients^8-11. A prospective trial by Zaid et al. (2020) demonstrated these advantages, showing: the non-inferiority of 3D-printed stents in terms of patient-reported outcomes, their comparable reproducibility in intraoral positioning, their low-cost production (average of 12 USD per stent) and reduced fabrication time (average of 8 hours per stent)(see Fig. 2)¹². Compared to the manual fabrication process, it is easy to see how digital 3D printing provides a cost-effective option for clinicians and patients!

Limitations of 3D Printed Oral Stents:

Despite promising results, there exist challenges limiting the integration of 3D-printed oral stents into clinical practice:

1. The quality of 3D-printed oral stents and post-processing time depend on the imaging quality of the oral anatomy — oral stent designs for 3D-printing can be generated using (a) CT imaging data, (b) surface scans of stone models, or (c) intraoral scanning. Segmentation of dental data from CT comes with numerous disadvantages due to presence of imaging artefacts, leading to a poor reconstruction of the dental anatomy with under/overestimation of tissue boundaries. Surface scanning method¹¹ provides a more accurate dental anatomy, however, requires the manual fabrication of the patient’s stone model, which are not readily available. Lastly, intraoral scanning offers a superior advantage in terms of quality and efficiency compared to (a) and (b), however, are expensive and requires more resources and the proper training of clinical personnels¹⁰.
2. Inter- and intra- variabilities of 3D-printed devices — there exists a wide range of biocompatible 3D-printing materials, technologies and parameters which offers users great flexibility in their design and manufacturing objectives. Unfortunately, this high number of variables opens up myriad of uncertainties concerning safety, durability, and compatibility^{13, 14}. As a general rule, users must utilize the same vendor material, 3D printing machine, as well as vendor-recommended 3D printing parameters. Furthermore, it is advised that users perform their own in-house testing and analysis to ensure that errors/uncertainties are properly accounted for. Common technologies utilized for fabricating oral stents includes stereolithography with biocompatible resin materials^{8, 10-12}. Some have utilized material extrusion technologies, using Polylactic Acid (PLA) filaments^{9, 15}.
3. The steep learning curve for cancer centers adopting this technology — most HNC centers offering oral stents still utilize manual processes which involves a hefty number of tools and equipment. In comparison to a digital dental lab involving 3D-printers, we can start to observe a stark difference in terms of space, techniques, personnels, equipment, and workflows. For existing point-of-care facilities, transitioning between two different methods requires the proper education and training of key stakeholders such as technicians and clinicians. To facilities aiming to provide stent devices to other domestic facilities, the proper coordination with teams across sterilization and logistics further plays an important role in its successful implementation in the clinic. On the other hand, companies offering 3D-printed oral stents enables an easier and straightforward process, requiring minimal training of technicians and clinical personnels.

What lies ahead is the intricate landscape of regulations and reimbursements. The successful integration of a medical device into clinical practice relies on securing approvals from regulatory bodies and garnering acceptance within the broader cancer care community. Despite limited clinical data in the current literature, our hope is that generation of robust and reliable clinical data from randomized trials will effectively demonstrate the safety, efficacy, and feasibility of 3D-printed oral stents compared to the standard of care treatment¹⁶. Until such clinical data becomes available, the adoption of this technology in clinical settings is likely to be limited, predominantly confined to a few well-resourced cancer research institutions.

For reimbursements, I suggest readers to read on the article titled “Financial Issues of 3D Printing in Hospitals – Guide”, which explores the complexity of finance and how key stakeholders may tackle issues concerning Category I, II, and III CPT codes, of which all plays a key role towards the proper reimbursement of medical devices fabricated via 3D printing technologies.

Below are recent developments in the areas of 3D-printed oral stents for HNC radiotherapy:

• A 3D-printed positioning oral stent device, ‘Stentra™’, developed by Kallisio has received its FDA 510(k) clearance, and is ready to be utilized in HNC patients receiving radiotherapy. This technology was licensed by an existing patent developed by researchers at MD Anderson Cancer Center, Cancer Physics and Engineering Laboratory.

• The National Cancer Institute is currently sponsoring a clinical trial evaluating the use of customized 3D printed oral stents during head and neck radiotherapy. The goal is to assess the effectiveness of these personalized stents in reducing radiation exposure to normal tissues.

• Adaptiiv, a Canadian medtech firm, partnered with HP and Varian to create 3D-printed personalized devices for radiation oncology. Its FDA-cleared Simple Bolus software designs custom bolus accessories conforming to patient anatomy, shielding healthy tissues from unnecessary radiation exposure during radiotherapy treatments.

• Similarly, 3D Systems developed their own 3D medical image processing software DICOM-to-PRINT (D2P®), offering clinicians an efficient workflow to create 3D-printable models from diagnostic patient imaging data. Leveraging this technology, 3D Systems introduced their VSP® Bolus solution, receiving its FDA 510(k) clearance in 2022, aiming to reduce tissue toxicities from Radiotherapy.

Conclusion:

3D-printed oral stents stand as a testament to progress in the interface of design, engineering, and healthcare, offering hope in mitigating the debilitating effects of RIOM. Intraoral scanners, CAD, and 3D printing are now becoming common in modern dental clinics around the globe due to their synergistic features involving the efficient and accurate acquisition of oral anatomy and the rapid prototyping capabilities of CAD and 3D printing technologies. Unsurprisingly, these state-of-the-art technologies will continue to advance oral cancer care for HNC radiotherapy and are well-positioned to transform manual fabrication processes into the digital realm.

Acknowledgements:

I want to acknowledge the mentorship and guidance of my mentor, Dr. Eugene Koay, at MD Anderson Cancer Centre and the continuous support of our patients and collaborators!

Author information:

Rance Tino, PhD., is a postdoctoral fellow at the Cancer Physics and Engineering Lab at MD Anderson Cancer Center, utilizing CAD, 3D printing and computational modeling technologies for applications in Radiation Oncology.

If you are interested to read more about the amazing applications of 3D printing in Dentistry, go check-out this article “Dental 3D printing – The Ultimate Guide”!

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References:

1.     Siegel, R. L.;  Giaquinto, A. N.; Jemal, A., Cancer statistics, 2024. CA: A Cancer Journal for Clinicians 2024, 74 (1), 12-49.

2.     Chi, A. C.;  Day, T. A.; Neville, B. W., Oral cavity and oropharyngeal squamous cell carcinoma—an update. CA: a cancer journal for clinicians 2015, 65 (5), 401-421.

3.     Elting, L. S.;  Cooksley, C. D.;  Chambers, M. S.; Garden, A. S., Risk, Outcomes, and Costs of Radiation-Induced Oral Mucositis Among Patients With Head-and-Neck Malignancies. International Journal of Radiation Oncology*Biology*Physics 2007, 68 (4), 1110-1120.

4.     McCullough, R. W., Actual duration of patient-reported mucositis: Far longer than 2 to 4 weeks and may be avoidable altogether. Korean J Clin Oncol 2016, 12 (1), 1-6.

5.     Singh, A.;  Rosen, E. B.;  Randazzo, J. D.;  Estilo, C. L.;  Gelblum, D. Y.; Huryn, J. M., Intraoral radiation stents—Primer for clinical use in head and neck cancer therapy. Head & Neck 2021, 43 (12), 4010-4017.

6.     Stieb, S.;  Perez-Martinez, I.;  Mohamed, A. S. R.;  Rock, S.;  Bajaj, N.;  Deshpande, T. S.;  Zaid, M.;  Garden, A. S.;  Goepfert, R. P.;  Cardoso, R.;  Ferrarotto, R.;  Reddy, J. P.;  Phan, J.;  Morrison, W. H.;  Rosenthal, D. I.;  Koay, E. J.;  Frank, S. J.;  Fuller, C. D.; Gunn, G. B., The impact of tongue-deviating and tongue-depressing oral stents on long-term radiation-associated symptoms in oropharyngeal cancer survivors. Clinical and Translational Radiation Oncology 2020, 24, 71-78.

7.     Rocha, B. A.;  Lima, L. M. C.;  Paranaíba, L. M. R.;  Martinez, A. d. S.;  Pires, M. B. d. O.;  de Freitas, E. M.;  Vilas Boas, C. V.; de Melo Filho, M. R., Intraoral stents in preventing adverse radiotherapeutic effects in lip cancer patients. Reports of Practical Oncology & Radiotherapy 2017, 22 (6), 450-454.

8.     Wilke, C. T.;  Zaid, M.;  Chung, C.;  Fuller, C. D.;  Mohamed, A. S. R.;  Skinner, H.;  Phan, J.;  Gunn, G. B.;  Morrison, W. H.;  Garden, A. S.;  Frank, S. J.;  Rosenthal, D. I.;  Chambers, M. S.; Koay, E. J., Design and fabrication of a 3D-printed oral stent for head and neck radiotherapy from routine diagnostic imaging. 3D Print Med 2017, 3 (1), 12.

9.     Cleland, S.;  Crowe, S. B.;  Chan, P.;  Chua, B.;  Dawes, J.;  Kenny, L.;  Lin, C. Y.;  McDowall, W. R.;  Obereigner, E.;  Poroa, T.;  Stewart, K.; Kairn, T., Development of a customisable 3D-printed intra-oral stent for head-and-neck radiotherapy. Technical Innovations & Patient Support in Radiation Oncology 2022, 23, 1-7.

10.   Bruno, J. S.;  Miranda-Silva, W.;  Guedes, V. d. S.;  Parahyba, C. J.;  Moraes, F. Y. d.; Fregnani, E. R., Digital Workflow for Producing Oral Positioning Radiotherapy Stents for Head and Neck Cancer. Journal of Prosthodontics 2020, 29 (5), 448-452.

11.   Zaid, M.;  Bajaj, N.;  Burrows, H.;  Mathew, R.;  Dai, A.;  Wilke, C. T.;  Palasi, S.;  Hergenrother, R.;  Chung, C.;  Fuller, C. D.;  Phan, J.;  Gunn, G. B.;  Morrison, W. H.;  Garden, A. S.;  Frank, S. J.;  Rosenthal, D. I.;  Andersen, M.;  Otun, A.;  Chambers, M. S.; Koay, E. J., Creating customized oral stents for head and neck radiotherapy using 3D scanning and printing. Radiation Oncology 2019, 14 (1), 148.

12.   Zaid, M.;  Koay, E. J.;  Bajaj, N.;  Mathew, R.;  Xiao, L.;  Agrawal, A.;  Fernandes, P.;  Burrows, H.;  Roach, M. A.;  Wilke, C. T.;  Chung, C.;  Fuller, C. D.;  Phan, J.;  Gunn, G. B.;  Morrison, W. H.;  Garden, A. S.;  Frank, S. J.;  Rosenthal, D. I.;  Andersen, M.;  Otun, A.; Chambers, M. S., A prospective parallel design study testing non-inferiority of customized oral stents made using 3D printing or manually fabricated methods. Oral Oncology 2020, 106, 104665.

13.   Tahayeri, A.;  Morgan, M.;  Fugolin, A. P.;  Bompolaki, D.;  Athirasala, A.;  Pfeifer, C. S.;  Ferracane, J. L.; Bertassoni, L. E., 3D printed versus conventionally cured provisional crown and bridge dental materials. Dental Materials 2018, 34 (2), 192-200.

14.   Craft, D. F.;  Kry, S. F.;  Balter, P.;  Salehpour, M.;  Woodward, W.; Howell, R. M., Material matters: analysis of density uncertainty in 3D printing and its consequences for radiation oncology. Medical physics 2018, 45 (4), 1614-1621.

15.   Ma, J.;  Chen, Z.;  Liu, S.;  Hu, W.;  Su, K.;  He, R.;  Zhou, P.;  Xiao, H.;  Ju, J.;  Hou, Q.;  Zhou, Y.; Wang, B., The application of 3D-printed oral stents in intensity-modulated radiotherapy for oropharyngeal cancer and their dosimetric effect on organs at risk. Eur J Med Res 2023, 28 (1), 367.

16. Tino, R., Roach, M. A., Fuentes, G. D., Agrawal, A., Zaid, M., Cooper, D. J., … & Koay, E. J. (2024). Development and clinical implementation of a digital workflow utilizing 3D-printed oral stents for patients with head and neck cancer receiving radiotherapy. Oral Oncology, 157, 106944.

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While FDM, SLA, two-photon laser, drop on demand are some of the most popular biofabrication methods, this “From Academia” issue includes three less well-known but trending methods that could be complementary or alternative to the typical 3D bioprinting process. The first article introduces a biofabrication method using ultrasound waves, also known as sonolithography. This gentle method can rapidly generate 2D cell patterns for a variety of materials, as well as act as a complementary technique to additive manufacturing where surface patterning combined with layer‐by‐layer fabrication can facilitate the generation of structures with more internal complexity. However, this method does not allow selectively targeting and manipulating individual cells. The second article addresses exactly that problem with a single cell bioprinting method using short laser pulses, which allow for the precise and efficient selection and positioning of individual mammalian cells, as well as transferring of specific cell/cells to a target surface with precision and high cell viability. The third publication was written in 2017, but we are anticipating the author’s upcoming paper in a few weeks. This paper reviews the principles behind a fabrication technique called melt eletrowriting (or electrostatic writing) and also compares it to an adjacent technique called electrospinning. The author also lists potential biomedical applications of this technique.

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino (info@3dheals.com) if you want to share relevant academic publications with us.

Sonolithography: In‐Air Ultrasonic Particulate and Droplet Manipulation for Multiscale Surface Patterning

Authored by Jenna M. Shapiro  Bruce W. Drinkwater  Adam W. Perriman  Mike Fraser. Advanced Materials Technologies. December 2 2020

Single Cell Bioprinting with Ultrashort Laser Pulses

Authored by Jun Zhang  Patrick Byers  Amelie Erben  Christine Frank  Levin Schulte‐Spechtel  Michael Heymann  Denitsa Docheva  Heinz P. Huber  Stefanie Sudhop  Hauke Clausen‐Schaumann. Advanced Functional Materials. March 26 2021

Melt electrowriting with additive manufacturing principles

Authored by Paul D. Dalton. Current Opinion in Biomedical Engineering. June 2017

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The post From Academia: Sonolithography, Single Cell Bioprinting, Melt Electrowriting appeared first on 3DHeals.

3D printing for perioperative planning has been around since the birth of STL. However, the medical community has gone through many milestones, and this “From Academia” blog highlights three recent publications demonstrating how the surgical communities are reinventing old surgical techniques using new 3D technologies, racing from 3D printed soft anatomical models, new 3D software tools, finite element analysis, to artificial intelligence and cloud computing. The first article is a review focusing on different applications of 3D printing in breast cancer management, ranging from visualization help to surgical guides that may be more superior to conventional guidance to post-surgical radiation treatment guidance. The second article is a research paper focusing on creating streamlined workflow leveraging improved, more automated segmentation processes (for soft tissues) and soft material 3D printing technologies to create better neurosurgical planning by creating 3D printed patient-specific brain tumour models. The final paper describes the use of affordable 3D printing technology to produce ready-to-use, sterilizable auricular carving and framework sizing templates to guide the perioperative sculpture of the cartilaginous framework during microtia reconstruction, considered one of the most challenging procedures in the field of reconstruction surgery.

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino ( info@3dheals.com ) if you want to share relevant academic publications with us.

Applications of 3D printing in breast cancer management

Authored by Arpine Galstyan, Michael J. Bunker, Fluvio Lobo, Robert Sims, James Inziello, Jack Stubbs, Rita Mukthar & Tatiana Kelil. 3D printing in Medicine. February 9 2021

Clinical application of patient-specific 3D printing brain tumor model production system for neurosurgery

Authored by Yun-Sik Dho, Doohee Lee, Teahyun Ha, So Young Ji, Kyung Min Kim, Ho Kang, Min-Sung Kim, Jin Wook Kim, Won-Sang Cho, Yong Hwy Kim, Young Gyu Kim, Sang Joon Park & Chul-Kee Park. Nature Scientific Reports. March 26 2021

Multiscale sterilizable 3D printed auricular templates to guide cartilaginous framework sizing and sculpture during autologous microtia reconstruction

Authored by Bushra Alhazmi, Feras Alshomer, Bassam Alawirdhi. JPRAS open. March 19 2021

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In this “From Academia” blog, we focus on a key ingredient for successful bioprinting, the bioinks. The first article is a recently published review that will lay the foundation of various bioprinting methods and focus on the natural, synthetic, or hybrid materials used as bioinks. This article also addresses the bioprinting technique’s challenges, limitations, and future directions. The second article explores how bioprinting and organoid technology can be merged to generate centimetre-scale tissues that have self-organized features, including lumens, branched vasculatures, and tubular intestinal epithelia with in vivo-like crypts and villus domains. This method could potentially be used to produce larger functional tissue with more geometry and cellular control. The third article introduces a new hydrogel bioink composed of partially digested, porcine cardiac decellularized extracellular matrix (cdECM), Laponite-XLG nanoclay, and poly(ethylene glycol)-diacrylate (PEG-DA). Here, the researchers show that 3D printed constructs with this new bioink demonstrate shape fidelity, adaptability to different printing conditions, and high cell viability following extrusion and photo-polymerization, highlighting the potential for applications in modelling both healthy and fibrotic cardiac tissue. 

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino (info@3dheals.com) if you want to share relevant academic publications with us.

Natural and Synthetic Bioinks for 3D Bioprinting

Authored by Dr. Roghayeh Khoeini  Dr. Hamed Nosrati  Dr. Abolfazl Akbarzadeh  Dr. Aziz Eftekhari  Dr. Taras Kavetskyy  Prof. Rovshan Khalilov  Dr. Elham Ahmadian  Dr. Aygun Nasibova  Dr. Pallab Datta  Dr. Leila Roshangar  Dr. Dante C. Deluca  Dr. Soodabeh Davaran  Prof. Magali Cucchiarini  Prof. Ibrahim T. Ozbolat. Advanced Nanobiomed Research. March 30 2021

Recapitulating macro-scale tissue self-organization through organoid bioprinting

Authored by Jonathan A. Brassard, Mike Nikolaev, Tania Hübscher, Moritz Hofer & Matthias P. Lutolf. Nature Materials, September 21 2020

3D bioprinting of mechanically tuned bioinks derived from cardiac decellularized extracellular matrix

Authored by Yu Jung Shin, Ryan T. Shafranek, Jonathan H. Tsui, Jelisha Walcott, Alshakim Nelson, Deok-Ho Kim. Acta Biomaterialia. January 1 2021

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The post From Academia: Bioprinting of Synthetic and Natural Bioinks appeared first on 3DHeals.

In this issue of “From Academia“, we include four recent research publications related to “seeing”, including articles focusing on creating smart contact lenses, cornea, glass optics, and microscope leveraging 3D printing technologies. In the first article, researchers presented a way to develop hydrogel-based contact lenses that can have biosensing capabilities, including sensing eye blinking (peristaltic pressure), PH, and Na+ level, adding another tool to the future wearable market. In the second article, researchers demonstrated how additive manufacturing of gradient index (GRIN) silica-titania glass via direct ink writing method could potentially create a variety of conventional and unconventional optical functions in a flat glass component with no surface curvature. In the third article, the researchers described a way to create a 3D corneal stroma using an orthogonally oriented pure electro-compacted collagen (EC). The researchers believe this technique could potentially be used to create a future full-thickness corneal replacement. In the final article, the authors presented UC2 (You. See. Too.), a low-cost, 3D-printed, open-source, modular microscopy toolbox. The authors demonstrate its versatility by realizing a complete microscope development cycle from concept to experimental phase and developing an open standard in optics to facilitate interfacing with various complementary platforms. 

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino (info@3dheals.com) if you want to share relevant academic publications with us.

Microengineered poly(HEMA) hydrogels for wearable contact lens biosensing

Authored by Yihang Chen, Shiming Zhang, Qingyu Cui, Jiahua Ni, Xiaochen Wang, Xuanbing Cheng, Halima Alem, Peyton Tebon, Chun Xu, Changliang Guo,  Rohollah Nasiri, Rosalia Moreddu, Ali K. Yetisen, Samad Ahadian, Nureddin Ashammakhi, Sam Emaminejad, Vadim Jucaud,   Mehmet R. Dokmeci  and  Ali Khademhosseini. Lab on a Chip. 13 October 2020

3D printed gradient index glass optics

Authored by Rebecca Dylla-Spears, Timothy D. Yee, Koroush Sasan, Du T. Nguyen, Nikola A. Dudukovic, Jason M. Ortega, Michael A. Johnson, Oscar D. Herrera, Frederick J. Ryerson and Lana L. Wong, Science Advances. 18 November 2020 

Biomimetic corneal stroma using electro-compacted collagen

Authored by Zhi Chen, Xiao Liu, Jingjing You, Yihui Song, Eva Tomaskovic-Crook, Gerard Sutton, Jeremy M.Crook, Gordon G.Wallace. Acta Biomaterialia, 1 September 2020 

A versatile and customizable low-cost 3D-printed open standard for microscopic imaging

Authored by Benedict Diederich, René Lachmann, Swen Carlstedt, Barbora Marsikova, Haoran Wang, Xavier Uwurukundo, Alexander S. Mosig & Rainer Heintzmann. Nature Communications. 25 November 2020

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The post From Academia: 3D Printing Contact Lenses, Optics, and Visualization appeared first on 3DHeals.

In this issue of “From Academia”, we include three recent publications introducing innovative ways to deliver drugs. In the first article, the researchers demonstrated 3DMNMEMS, a novel device that combines 3D printing, microneedles (MNs), and Microelectromechanical Systems (MEMS). This device allows for versatile and controllable transdermal drug delivery, for example, the delivery of insulin. In the second article, the authors presented a one-step fabrication process of a microfluidic chip for drug dissolution assays based on 3D printing technology. The authors suggest that this method could be a reliable tool for drug release assays during the early research stages. The final publication is a review article focusing on past publications discussing the current applications of 3D-printed porous tantalum (3D-P-p-Ta), a novel drug delivery strategy, in drug delivery systems to repair hard tissue defects, as well as the limitations of existing data and potential future research directions.

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino (info@3dheals.com) if you want to share relevant academic publications with us.

A novel 3D printed hollow microneedle microelectromechanical system for controlled, personalized transdermal drug delivery

Authored by Sophia N. Economidou, Jasim Uddin, Manual J. Marques, Dennis Douroumis, Wan Ting Sow, Huaqiong Li, Andrew Reid, James F.C. Windmill, Adrian Podoleanu. Additive Manufacturing. February 2021

3D Printed Microfluidic Devices for Drug Release Assays

Authored by Benzion Amoyav, Yoal Goldstein, Eliana Steinberg, Ofra Benny. MDPI Pharmaceutics. 19 December 2020

3D-printed porous tantalum: recent application in various drug delivery systems to repair hard tissue defects

Authored by Long Hua,Ting Lei,Hu Qian,Yu Zhang,Yihe Hu &Pengfei Lei. Expert Opinion on Drug Delivery. November 2020

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3DHEALS Guides (Collective) – This is where we dive deep into subjects that you will find helpful for your projects and career.

3DEALS Expert Corner (Collective) – This is where we invite field experts to write their perspectives in a first-person narrative. To write for this column, please email: info@3dheals.com

3DHEALS From Academia (Collective) – This section features recent, relevant, close to commercialization academic publications in the space of healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Other similar articles

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In this issue of “From Academia”, we included two publications that connect the world of radiology and medical 3D printing in very creative ways. In the first article, the authors use an ultrasonic elastography technique that measures the effective density and the dynamic bulk modulus elastography (EBME) of 3D printed anatomical models using voxelated materials and 3D printed by J750. This could have important implications for future quality control of 3D printed medical devices using the voxel print technique. In the second article, The researchers demonstrated an inexpensive method of reproducing a full spectrum of adult bone-like anthropomorphic femur phantom slab using a new interlace deposition extrusion method of standard PLA and Fe-PLA filaments. This model can achieve the required CT appearance (based on HU) for a range of bony structures and soft tissues while providing patient-specificity. Such phantom has applications in surgical guidance, diagnostic imaging, as well as end-to-end dosimetry in radiotherapy.

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino (info@3dheals.com) if you want to share relevant academic publications with us.

Manufacturing and Characterization of Hybrid Bulk Voxelated Biomaterials Printed by Digital Anatomy 3D Printing

Authored by Hyeonu Heu, Yuqi Jin, David Yang, Christopher Wier, Aaron Minard, Narendra B. Dahotre, Arup Neogi. MDPI Polymers. 30 December 2020

The Interlace Deposition Method of Bone Equivalent Material Extrusion 3D Printing for Imaging in Radiotherapy

Authored by Rance Tino, Adam Yeo, Milan Brandt, Martin Leary, Tomas Kron. Materials & Design. 1 February 2021

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3D Printing and Bioprinting For Cancer Care – Guide

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Medical 3D Printing for Surgery: Anatomical Models and Surgical Guides

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In this issue of “From Academia”, we include three recent publications focusing on medical 3D printing for surgical planning, either using 3D printed anatomical models or surgical guides. The first is a review article focusing on cost/benefit analysis of using 3D printing in orthopedic and maxillofacial surgery, primarily in terms of operating room time saved. This is very relevant to our guide focusing on 3D printing in hospitals. The second study focuses on a case study using an innovative patient-specific instrument guide (PSIG) for the safe removal of a skull bone tumor. The final article introduces a 2-in-1 patient-specific 3D printed laminectomy surgical guide with integrated pedial screw drill guides.

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino (tino.rance@gmail.com) if you want to share relevant academic publications with us.

Medical 3D Printing Cost-Savings in Orthopedic and Maxillofacial Surgery: Cost Analysis of Operating Room Time Saved with 3D Printed Anatomic Models and Surgical Guides

Authored by David H. Ballard, Patrick Mills, Richard Duszak Jr., Jeffery A. Weisman, Frank J. Rybicki, Pamela K. Woodward. Academic Radiology. August 2020

Printing a patient-specific instrument guide for skull osteoma management

Authored by Tien-Hsiang Wang, Li-Ying Huang, Yu-Cheng Hung, Te-Han Wang, Wen-Chan, Fang-Yau Chiu, Shyh-Jen Wang, Wei-Ming Chen. Journal of the Chinese Medical Association, October 2020

The Development of Novel 2-in-1 Patient-Specific, 3D-Printed Laminectomy Guides with Integrated Pedicle Screw Drill Guides

Authored by Andrew Kanawati, Renan Jose Rodrigues Fernandes, Aaron Gee, Jennifer Urquhart, Fawaz Siddiqi, Kevin Gurr, Christopher S. Baley, Parham Rasoulinejad. World Neurosurgery. February 1 2021

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Other From Academia Blogs

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There has been an uptick in research activities focusing on 3D bioprinting for bone regeneration. In this issue of “From Academia”, we include four recent publications tackling the issue from different angles. The first article focuses on a new 3D printing composite using silicone resing derived larnite/C scaffold to create new regeneration and treatment strategies for bone tumor patients. The second study focuses on a new bio-ink for 3D bioprinting bone, nanoengineered ionic covalent entanglement (NICE) bioink formulation, which not only showed good printability, mechanical properties, biodegradability, but also the ability to induce endochondral differentiation of encapsulated human mesenchymal stem cells (hMSCs) in the absence of an osteoinductive agent on a genetic level. In the third study, researchers developed a new PLA-based composite formulation that could be used to produce bone scaffold and regeneration. In the last article, a new iron-based ink formulation, as well as matching 3D printing, de-binding, and sintering conditions, was developed to create iron scaffolds with a porosity of 67%, pore interconnectivity of 96%, and a strut density of 89% after sintering. The study shows the great potential of extrusion-based 3D printed porous iron to be further developed as a biodegradable bone substituting biomaterial.

“From Academia” features recent, relevant, close to commercialization academic publications. Subjects include but not limited to healthcare 3D printing, 3D bioprinting, and related emerging technologies.

Email: Rance Tino (info@3dheals.com) if you want to share relevant academic publications with us.

Silicone resin derived larnite/C scaffolds via 3D printing for potential tumor therapy and bone regeneration

Authored by Shengyang Fu, Haoran Hu, Jiajie Chen, Yufang Zhu, Shichang Zhao. Chemical Engineering Journal. 15 February 2020

Nanoengineered Osteoinductive Bioink for 3D Bioprinting Bone Tissue

Authored by David Chimene, Logan Miller, Lauren M. Cross, Manish K. Jaiswal, Irtisha Singh, and Akhilesh K. Gaharwar. ACS Applied Materials & Interfaces. 24 February 2020 

Biocompatible heterogeneous bone incorporated with polymeric biocomposites for human bone repair by 3D printing technology

Authored by Meiling Wan  Shuifeng Liu  Da Huang  Yang Qu  Yang Hu  Qisheng Su  Wenxu Zheng  Xianming Dong  Hongwu Zhang  Yen Wei  Wuyi Zhou. Journal of Applied Polymer Science. 24 November 2020

Extrusion-based 3D printed biodegradable porous iron

Authored by N.E. Putra, M.A. Leeflang, M. Minneboo, P. Taheri, L.E. Fratila-Apachitei, J.M.C. Mol, J. Zhou, A.A. Zadpoor. Acta Biomaterialia. May 2020

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An Introduction to Scaffolds for Tissue Engineering of the Bone and Cartilage

The post From Academia: 3D Bioprinting for Bone Regeneration appeared first on 3DHeals.

3D Printing (3DP), also referred to as Additive Manufacturing (AM), offers cost-effective and customizable solutions for the creation of anthropomorphic radiotherapy phantoms. These phantoms are employed in vitro to aid in the treatment planning of cancer patients and ensure the quality assurance (QA) of novel radiotherapy techniques. By utilizing 3D printing technology, these phantoms enable the experimental validation of personalized radiation doses and help minimize the impact of ionizing radiation to surrounding healthy tissues.

Modern radiotherapy involves the use of Computed Tomography (CT) imaging, 3D-treatment planning, and the implementation of comprehensive QA processes to produce highly conformal dose distributions and ensure the safe and accurate delivery of the planned treatment. It is common to manufacture phantoms using the molding and casting process, that emulates the radiation properties of the average human tissue as radiation dose cannot be directly measured from patients.

QA processes are often conducted using phantoms ranging from simple geometries (i.e., blocks) to anthropomorphics, in conjunction with various dose measurement tools like thermoluminescent dosimeters (TLDs), radiochromic films, or ion chambers. Well constructed anthropomorphic phantoms available in the market consists of tissue-equivalent materials that provides a good representation of the average person’s cartilage, spinal cord, spinal disks, lung, brain, sinus, bone, and soft tissue, with varying degrees of complexity for clinically relevant sex and ages. Despite this, a common theme behind these phantoms are their costs (i.e., specialized tissue-equivalent materials, high manufacturing expenses and lengthy lead-times) and their limited adaptability aka “one-size-fits-all”. These phantoms only replicate average human proportions, lack personalized tissue heterogeneity, and fail to accommodate pathological features, thus limiting the potential of personalized treatments enabled by the advancing radiotherapy technology. For instance, the current radiotherapy phantom market lacks options for emulating obese patients and offers limited ranges for simulating pediatric patients [1]. With the growing amount of 3DP literature in the healthcare sector, is it possible to customize functional phantoms to address such limitations?

This article discusses some of the basic concepts surrounding the manufacture of 3DP phantoms, their clinical significance and requirements, their associated manufacturing techniques and materials, and the future of 3DP phantoms for radiotherapy use.

Anthropomorphic radiotherapy phantoms for treatment planning.

The treatment planning procedure is a significant part of radiotherapy, which determines the optimal treatment parameters to be used for the management of a patient’s disease via radiotherapy means. These treatment parameters include target volume, dose-limiting structures, treatment volume, dose prescription, dose fractionation, dose distribution, the positioning of the patient, treatment machine settings, and adjuvant therapies (e.g. chemotherapy, hormone therapy, targeted therapy, or biological therapy) [1]

Other than QA, phantoms also act as a human proxy to experimentally visualize and evaluate treatment options tailored for the patient. This importance signifies the current limitations of anthropomorphic phantoms as they only follow the average body proportion and radiation attenuations of a ‘healthy’ person, and lack patient-specific pathological features, particularly for the emulation of lesion shape, density, and positioning [2]. Therefore, these limitations provide a significant opportunity for the 3D printing technology in highlighting low manufacturing costs and phantom customization.

Customization of phantoms enabled by 3DP.

3D printing provides opportunities for the inexpensive manufacture of customizable devices as observed from the current literature not only for radiotherapy phantoms but also for other radiotherapy devices including bolus and compensators to achieve personalized dose distributions for irregular surfaces; electron beam shielding devices to block ionizing beams and scattered rays; immobilizers to secure patients during treatment to avoid unnecessary movements during treatment and; brachytherapy moulds to allow targeted radiation treatment using catheters to allow the insertion of radioactive seeds close to the lesion [3,4].

Novel 3D printing workflows have been developed to accommodate imaging tissue-like heterogeneity utilising 3D printing materials, via modification of infill parameters, and the in-house development of materials to modify their radiation attenuation properties.

Types of 3DP phantoms.

Early versions of additively manufactured radiotherapy phantoms were manufactured as-shell phantoms, which are hollowed phantoms filled with various tissue-equivalent materials (sawdust, silicone gels, cork).

The emergence of better AM technologies has attracted interest in exploring the simulation of human tissue heterogeneity, classified as as-printed phantoms. Heterogeneity in printed phantoms can be achieved using material extrusion (MEX) (well known as fused deposition modeling (FDM)) printing parameters such as infilling patterns and percentage, printing nozzle size, temperature, and more recently, the modification of material extrusion rate.

Furthermore, contrast variations can also be achieved by constructing phantoms with two or more different AM materials (multiple material printing); doping filaments with high-density materials such as bismuth and barium sulfate to increase the observed HU range; and the use of controlled voided structures within the manufactured phantoms to precisely controlled HU values.

Recent studies have illustrated the combination of these manufactured phantoms with commercially available motion platforms and in-house motion devices to further stimulate body movements, especially the thorax’s respiratory movements (classified as 4D-AM phantoms) (see Figure 3). See more recent reviews of 3D printing phantoms in the literature from [3, 4, 5, 7]. 

Figure 3 below illustrates more in detail that 3DP phantoms are divided into two manufacturing processes, (1) direct manufacturing process utilizing only commercial or in-house 3DP materials for manufacture phantoms, and (2) indirect manufacturing process utilizing 3DP materials (commercial or in-house) and are assembled with tissue-substitutes (non-3DP materials) to manufacture phantoms). These 3DP phantoms are categorized into a solid phantom, a deformable phantom utilizing deformable 3DP materials, or a 4D phantom, which are either solid or deformable phantom attached to a motion platform to simulate patient movements.

Video 1. Comparison of 3DP bone phantom with the associated patient CT dataset [8].

Clinical requirements and implications.

More recently, printing guidelines and recommendations for 3DP in medicine have been developed by the SIG (Special Interest Group on 3D printing), a group representing the Radiological Society of North America [9]. The guidelines and recommendations are divided into four main processes including:

1. Medical image acquisition – commonly used imaging modality involves CT or MRI. Associated patient data should have sufficient spatial resolution to accurately represent anatomy to be modelled.
2. Image data preparation and manipulation – includes image segmentation, 3D CAD design, and file documentation.
3. Generation of the 3D-printed model –involves the printing process, post-processing, and model inspection.
4. Quality Control program – involves the delivery and discussion with referring physicians, pre-operative planning, material biocompatibility, cleaning, and sterilisation, and clinical appropriateness. 

Regarding printing materials, it is essential to consider the photoelectric and Compton effects when comparing result outputs with human tissues. Photoelectric effect serves as the dominant phenomena at low x-ray energies ranging below 200 KeV, hence for imaging modalities (CT, MRI, PET). At higher x-ray energies up to 10 MeV, Compton effects can be considered as the dominant phenomena, where material attenuation differs depending on their elemental composition, signifying how radiation doses are distributed [1]. Ideally, 3DP phantoms aim to simulate not only the patient’s proportion and pathological features but also both the imaging attenuation of human tissues, the photoelectric effect, and the dose attenuation of tissues, the Compton effect.

Also, for any given 3D printing material to be tissue or water equivalent, it must have the same effective atomic number, number of electrons per gram, and mass density. However, since the Compton effect is the predominant mode of interaction for MV photon beams in the clinical range, the necessary condition for water equivalence for such beams is the same electron density (number of electrons per cubic centimetre) as that of water.

The future of 3DP phantoms.

Despite lower manufacturing costs and complex geometrical capabilities of 3D printing in developing anthropomorphic radiotherapy phantoms, there exists numerous uncertainties with regards to their reproducibility and sustainability.

At present, the commonly utilized 3DP technology for developing phantoms, MEX, is still yet to be fully exploited to its full potential for manufacturing clinically viable phantoms for routine use. MEX comes with inherent limitations in comparison with other printing techniques such as Material jetting technologies (MJT) and Stereolithography (SLA) where significant void defects are observed, which in turn produces structurally weak and non-uniform dense objects affecting the phantoms reproducibility and sustainability.

In comparison to the huge growth of 3D printed surgical guides and implants in the healthcare industry, 3DP phantoms will soon be able to compete clinically and be more accepted globally as clinicians and engineers work towards quantifying the associated manufacturing uncertainties, explore innovative 3DP methods, and tissue-equivalent materials for the customization of 3DP phantoms, and its implementation for complex case studies comparing 3DP phantoms and commercial phantoms. Furthermore, it is also recommended that proper documentation of these 3DP phantoms (i.e. printing parameters, printing machine description, the body-site of application, imaging modality used, material and printing costs, printing and time, printing workflow, post-processing procedures) be implemented as it will play a significant role in providing guidance for developing clinical regulations and cost reimbursements for such devices in the future.

Acknowledgements:

Some references in this work are a collection of collaborative efforts conducted during my PhD at RMIT’s Centre for Additive Manufacturing (RCAM) under the supervision of Professor Martin Leary and Distinguished Professor. Milan Brandt and Sir Peter MacCallum Cancer Centre physical sciences department involving Professor Tomas Kron and Senior medical physicist, Dr. Adam Yeo.

References:

[1] Khan, F.M., Gibbons, J.P. and Sperduto, P.W., 2016. Khan’s treatment planning in radiation oncology. Lippincott Williams & Wilkins.

[2] Kron, T., Ungureanu, E., Antony, R., Hardcastle, N., Clements, N., Ukath, J., Fox, C., Lonski, P., Wanigaratne, D. and Haworth, A., 2017. Patient specific quality control for Stereotactic Ablative Body Radiotherapy (SABR): it takes more than one phantom. In Journal of Physics: Conference Series (Vol. 777, No. 1, p. 012017). IOP Publishing.

[3] Tino, R., Yeo, A., Leary, M., Brandt, M. and Kron, T., 2019. A systematic review on 3D-printed imaging and dosimetry phantoms in radiation therapy. Technology in cancer research & treatment, 18, p.1533033819870208.

[4] Tino, R., Leary, M., Yeo, A., Kyriakou, E., Kron, T. and Brandt, M., 2020. Additive manufacturing in radiation oncology: a review of clinical practice, emerging trends and research opportunities. International Journal of Extreme Manufacturing, 2(1), p.012003.

[5] Leary, M., Kron, T., Keller, C., Franich, R., Lonski, P., Subic, A. and Brandt, M., 2015. Additive manufacture of custom radiation dosimetry phantoms: An automated method compatible with commercial polymer 3D printers. Materials & Design, 86, pp.487-499.

[6] Leary, M., Tino, R., Keller, C., Franich, R., Yeo, A., Lonski, P., Kyriakou, E., Kron, T. and Brandt, M., 2020. Additive manufacture of lung equivalent anthropomorphic phantoms: a method to control hounsfield number utilizing partial volume effect. Journal of Engineering and Science in Medical Diagnostics and Therapy, 3(1).

[7] Filippou, V. and Tsoumpas, C., 2018. Recent advances on the development of phantoms using 3D printing for imaging with CT, MRI, PET, SPECT, and ultrasound. Medical physics, 45(9), pp.e740-e760.

[8] Tino, R., Yeo, A., Brandt, M., Leary, M. and Kron, T., 2021. The interlace deposition method of bone equivalent material extrusion 3D printing for imaging in radiotherapy. Materials & Design, 199, p.109439.

[9] Chepelev, L., Wake, N., Ryan, J., Althobaity, W., Gupta, A., Arribas, E., Santiago, L., Ballard, D.H., Wang, K.C., Weadock, W. and Ionita, C.N., 2018. Radiological Society of North America (RSNA) 3D printing Special Interest Group (SIG): guidelines for medical 3D printing and appropriateness for clinical scenarios. 3D printing in medicine, 4(1), pp.1-38.

About the Author:

Rance Tino

Rance Tino attained a Bachelor of Engineering (Biomedical Engineering)(Honours) at the Royal Melbourne Institute of Technology (RMIT) in 2017. Since graduation, Rance has continued the academic pathway at RMIT and have recently completed his PhD with the Victoria Comprehensive Cancer Centre (VCCC), Peter MacCallum Physical Sciences department in developing a customizable Radiotherapy Phantoms using 3D printing for end-to-end testing of personalised treatment plans.

Related Articles:

3D Printing and Bioprinting For Cancer Care – Guide

From Academia: Bioprinted Cancer Models, Microprinted Imaging Probe, 3DTech for Congenital Heart Disease

From Academia: Four-axis 3D printing, Efficacy of 3D printed model for breast cancer reconstruction, and Cultured Meat

3D Printing for Cancer Treatment – Radiation Therapy Liver Phantom

The post 3D Printing of Customizable Phantoms in Radiation Oncology appeared first on 3DHeals.