Process,Material,and Regulatory Considerations for 3D Printed Medical Devices and Tissue Constructs

Three-dimensional(3D)printing is a highly automated platform that facilitates material deposition in a layer-by-layer approach to fabricate pre-defined 3D complex structures on demand.It is a highly promising technique for the fabrication of personalized medical devices or even patient-specific tissue constructs.Each type of 3D printing technique has its unique advantages and limitations,and the selection of a suitable 3D printing technique is highly dependent on its intended application.In this review paper,we present and highlight some of the critical processes(printing parameters,build orientation,build location,and support structures),material(batch-to-batch consistency,recycling,protein adsorption,biocompatibility,and degradation properties),and regulatory considerations(sterility and mechanical properties)for 3D printing of personalized medical devices.The goal of this review paper is to provide the readers with a good understanding of the various key considerations(process,material,and regulatory)in 3D printing,which are critical for the fabrication of improved patient-specific 3D printed medical devices and tissue constructs.

A Review on the 3D Printing of Functional Structures for Medical Phantoms and Regenerated Tissue and Organ Applications

Medical models, or ＂phantoms,＂ have been widely used for medical training and for doctor-patient interactions. They are increasingly used for surgical planning, medical computational models, algorithm verification and validation, and medical devices development. Such new applications demand high-fidelity, patient-specific, tissue-mimicking medical phantoms that can not only closely emulate the geometric structures of human organs, but also possess the properties and functions of the organ structure. With the rapid advancement of three-dimensional （3D） printing and 3D bioprinting technologies, many researchers have explored the use of these additive manufacturing techniques to fabricate functional medical phantoms for various applications. This paper reviews the applications of these 3D printing and 3D bioprinting technologies for the fabrication of functional medical phantoms and bio-structures. This review specifically discusses the state of the art along with new developments and trends in 3D printed functional medical phantoms （i.e., tissue-mimicking medical phantoms, radiologically relevant medical phantoms, and physiological medical phantoms） and 3D bio-printed structures （i.e., hybrid scaffolding materials, convertible scaffolds, and integrated sensors） for regenerated tissues and organs.

Application and Development of 3D Printing in Medical Field

Different from reduction manufacturing and equal manufacturing, 3D printing is an additive manufacturing method, which transforms 3D model into 2D cross-section data to form entity layer by layer. This makes its processing not limited by complexity of the design model and number of the manufacturing products. It is very suitable for the medical field with high customization requirements. In fact, application of 3D printing technology in the medical field is particularly noticeable. In this paper, application and development of 3D printing technology are reviewed in medical model, rehabilitation equipment, tissue engineering, medical hygiene materials, lab-on-chip. Its applications include medical education, surgical planning, prosthesis customization, tissue culture and biosensor manufacturing and so on. Its wide application is due to its digital model, which makes the whole manufacturing process easier to digitize, so it is more conductive to updating and customization of products via 3D printing.

3D‑Printed Carbon‑Based Conformal Electromagnetic Interference Shielding Module for Integrated Electronics

Electromagnetic interference shielding(EMI SE)modules are the core com-ponent of modern electronics.However,the tra-ditional metal-based SE modules always take up indispensable three-dimensional space inside electronics,posing a major obstacle to the integra-tion of electronics.The innovation of integrating 3D-printed conformal shielding(c-SE)modules with packaging materials onto core electronics offers infinite possibilities to satisfy ideal SE func-tion without occupying additional space.Herein,the 3D printable carbon-based inks with various proportions of graphene and carbon nanotube nanoparticles are well-formulated by manipulating their rheological peculiarity.Accordingly,the free-constructed architectures with arbitrarily-customized structure and multifunctionality are created via 3D printing.In particular,the SE performance of 3D-printed frame is up to 61.4 dB,simultaneously accompanied with an ultralight architecture of 0.076 g cm^(-3) and a superhigh specific shielding of 802.4 dB cm3 g^(-1).Moreover,as a proof-of-concept,the 3D-printed c-SE module is in situ integrated into core electronics,successfully replacing the traditional metal-based module to afford multiple functions for electromagnetic compatibility and thermal dissipa-tion.Thus,this scientific innovation completely makes up the blank for assembling carbon-based c-SE modules and sheds a brilliant light on developing the next generation of high-performance shielding materials with arbitrarily-customized structure for integrated electronics.

Additive manufacturing frontier： 3D printing electronics

3D printing is disrupting the design and manufacture of electronic products. 3D printing electronics offers great potentialto build complex object with multiple functionalities. Particularly, it has shown the unique ability to make embedded electronics,3D structural electronics, conformal electronics, stretchable electronics, etc. 3D printing electronics has beenconsidered as the next frontier in additive manufacturing and printed electronics. Over the past five years, a large numberof studies and efforts regarding 3D printing electronics have been carried out by both academia and industries. In thispaper, a comprehensive review of recent advances and significant achievements in 3D printing electronics is provided.Furthermore, the prospects, challenges and trends of 3D printing electronics are discussed. Finally, some promising solutionsfor producing electronics with 3D printing are presented.

Balancing the customization and standardization:exploration and layout surrounding the regulation of the growing field of 3D-printed medical devices in China

Medical devices are instruments and other tools that act on the human body to aid clinical diagnosis and disease treatment,playing an indispensable role in modern medicine.Nowadays,the increasing demand for personalized medical devices poses a significant challenge to traditional manufacturing methods.The emerging manufacturing technology of three-dimensional(3D)printing as an alternative has shown exciting applications in the medical field and is an ideal method for manufacturing such personalized medical devices with complex structures.However,the application of this new technology has also brought new risks to medical devices,making 3D-printed devices face severe challenges due to insufficient regulation and the lack of standards to provide guidance to the industry.This review aims to summarize the current regulatory landscape and existing research on the standardization of 3D-printed medical devices in China,and provide ideas to address these challenges.We focus on the aspects concerned by the regulatory authorities in 3D-printed medical devices,highlighting the quality system of such devices,and discuss the guidelines that manufacturers should follow,as well as the current limitations and the feasible path of regulation and standardization work based on this perspective.The key points of the whole process quality control,performance evaluation methods and the concept of whole life cycle management of 3D-printed medical devices are emphasized.Furthermore,the significance of regulation and standardization is pointed out.Finally,aspects worthy of attention and future perspectives in this field are discussed.

Acoustical properties of a 3D printed honeycomb structure filled with nanofillers:Experimental analysis and optimization for emerging applications

The novelty of this research lies in the successful fabrication of a 3D-printed honeycomb structure filled with nanofillers for acoustic properties,utilizing an impedance tube setup in accordance with ASTM standard E 1050-12.The Creality Ender-3,a 3D printer,was used for printing the honeycomb structures,and polylactic acid(PLA)material was employed for their construction.The organic,inorganic,and polymeric compounds within the composites were identified using fourier transformation infrared(FTIR)spectroscopy.The structure and homogeneity of the samples were examined using a field emission scanning electron microscope(FESEM).To determine the sound absorption coefficient of the 3D printed honeycomb structure,numerous samples were systematically developed using central composite design(CCD)and analysed using response surface methodology(RSM).The RSM mathematical model was established to predict the optimum values of each factor and noise reduction coefficient(NRC).The optimum values for an NRC of 0.377 were found to be 1.116 wt% carbon black,1.025 wt% aluminium powder,and 3.151 mm distance between parallel edges.Overall,the results demonstrate that a 3Dprinted honeycomb structure filled with nanofillers is an excellent material that can be utilized in various fields,including defence and aviation,where lightweight and acoustic properties are of great importance.

3D Printed Multi-material Medical Phantoms for Needle-tissue Interaction Modelling of Heterogeneous Structures

The fabrication of multi-material medical phantoms with both patient-specificity and realistic mechanical properties is of great importance for the development of surgical planning and medical training.In this work,a 3D multi-material printing system for medical phantom manufacturing was developed.Rigid and elastomeric materials are firstly combined in such application for an accurate tactile feedback.The phantom is designed with multiple layers,where silicone ink,Thermoplastic Polyurethane(TPU),and Acrylonitrile Butadiene Styrene(ABS)were chosen as printing materials for skin,soft tissue,and bone,respectively.Then,the printed phantoms were utilized for the investigation of needle-phantom interaction by needle insertion experiments.The mechanical needle-phantom interaction was characterized by skin-soft tissue interfacial puncture force,puncture depth,and number of insertion force peaks.The experiments demonstrated that the manufacturing conditions,i.e.the silicone grease ratio,interfacial thickness and the infill rate,played effective roles in regulating mechanical needle-phantom interaction.Moreover,the influences of material properties,including interfacial thickness and ultimate stress,on needle-phantom interaction were studied by finite element simulation.Also,a patient-specific forearm phantom was printed,where the anatomical features were acquired from Computed Tomography(CT)data.This study provided a potential manufacturing method for multi-material medical phantoms with tunable mechanical properties and offered guidelines for better phantom design.

Recent advances in meniscus-on-demand three-dimensional micro-and nano-printing for electronics and photonics

The continual demand for modern optoelectronics with a high integration degree and customized functions has increased requirements for nanofabrication methods with high resolution,freeform,and mask-free.Meniscus-on-demand three-dimensional(3D)printing is a high-resolution additive manufacturing technique that exploits the ink meniscus formed on a printer nozzle and is suitable for the fabrication of micro/nanoscale 3D architectures.This method can be used for solution-processed 3D patterning of materials at a resolution of up to100 nm,which provides an excellent platform for fundamental scientific studies and various practical applications.This review presents recent advances in meniscus-on-demand 3D printing,together with historical perspectives and theoretical background on meniscus formation and stability.Moreover,this review highlights the capabilities of meniscus-on-demand 3D printing in terms of printable materials and potential areas of application,such as electronics and photonics.

A desktop customised 3D printer with dual extruders to produce electronic circuitry

3D printing has opened new horizons for the manufacturing industry in general, and 3D printers have become the tools for technological advancements. There is a huge divide between the pricing of industrial and desktop 3D printers with the former being on the expensive side capable of producing excellent quality products and latter being on the low-cost side with moderate quality results. However, there is a larger room for improvements and enhancements for the desktop systems as compared to the industrial ones. In this paper, a desktop 3D printer called Prusa Mendel i2 has been modified and integrated with an additional extruder so that the system can work with dual extruders and produce bespoke electronic circuits. The communication between the two extruders has been established by making use of the In-Chip Serial Program- ming port on the Arduino Uno controlling the printer. The biggest challenge is to control the flow of electric paint （to be dispensed by the new extruder） and CFD （Computa- tional Fluid Dynamics） analysis has been carried out to ascertain the optimal conditions for proper dispensing. The final product is a customised electronic circuit with the base of plastic （from the 3D printer＇s extruder） and electronic paint （from the additional extruder） properly dispensed to create a live circuit on a plastic platform. This low-cost enhancement to a desktop 3D printer can provide a new prospect to produce multiple material parts where the additional extruder can be filled with any material that can be properly dispensed from its nozzle.

Artificial intelligence-based medical image segmentation for 3D printing and naked eye 3D visualization

Image segmentation for 3D printing and 3D visualization has become an essential component in many fields of medical research,teaching,and clinical practice.Medical image segmentation requires sophisticated computerized quantifications and visualization tools.Recently,with the development of artificial intelligence(AI)technology,tumors or organs can be quickly and accurately detected and automatically contoured from medical images.This paper introduces a platform-independent,multi-modality image registration,segmentation,and 3D visualization program,named artificial intelligence-based medical image segmentation for 3D printing and naked eye 3D visualization(AIMIS3D).YOLOV3 algorithm was used to recognize prostate organ from T2-weighted MRI images with proper training.Prostate cancer and bladder cancer were segmented based on U-net from MRI images.CT images of osteosarcoma were loaded into the platform for the segmentation of lumbar spine,osteosarcoma,vessels,and local nerves for 3D printing.Breast displacement during each radiation therapy was quantitatively evaluated by automatically identifying the position of the 3D printed plastic breast bra.Brain vessel from multimodality MRI images was segmented by using model-based transfer learning for 3D printing and naked eye 3D visualization in AIMIS3D platform.

3D printing applications for healthcare research and development

There is a growing demand for customised,biocompatible,and sterilisable components in the medical busi-ness.3D Printing is a disruptive technology for healthcare and provides significant research and development avenues.Simple 3D printing service gives patients low-cost individualised prostheses,implants,and gadgets,en-abling surgeons to operate more effectively with customised equipment and models;and assisting medical device manufacturers in developing new and faster goods.3D printed tissue pieces can overcome various challenges and may eventually allow medication companies to streamline research and development.In the long run,it may also assist in lowering prices and making medicines more accessible and effective for everybody.There is a growing corpus of research on the advantages of employing 3D printed anatomic models in teaching and training.The capacity to 3D printing individual anatomical diseases for practical learning is one of the funda-mental contrasts between utilising 3D and regular anatomical models.3D printing is very appealing for producing patient-specific implants.This literature review-based paper explores the role of 3D printing and 3D bioprinting in healthcare.It briefs the need and progressive steps for implementing 3D printing in healthcare and presented various facilities and enablers of 3D printing for the healthcare sector.Finally,this paper identifies and discusses the significant applications of 3D printing for healthcare research and development.3D printing services can be deployed to easily construct complex geometries in plastic or metal with good precision.This results in improved prototypes,lower costs,and lower part processing times.They can now physically create with natural materials,previously unattainable with prior technologies.Every hospital should have 3D printers in the future,allowing new organs/parts to be developed in-house.

A nonradiographic strategy to real-time monitor the position of three-dimensional-printed medical orthopedic implants by embedding superparamagnetic Fe_(3)O_(4) particles

Monitoring the position of orthopedic implants in vivo is paramount for enhancing postoperative rehabilitation.Traditional radiographic methods,although effective,pose inconveniences to patients in terms of specialized equipment requirements and delays in rehabilitation adjustment.Here,a nonradiographic design concept for real-time and precisely monitoring the position of in vivo orthopedic implants is presented.The monitoring system encompasses an external magnetic field,a three-dimensional(3D)-printed superparamagnetic intervertebral body fusion cage(SIBFC),and a magnetometer.The SIBFC with a polyetheretherketone framework and a superparamagnetic Fe_(3)O_(4) component was integrally fabricated by the high-temperature selective laser sintering technology.Owing to the superparamagnetic component,the minor migration of SIBFC within the spine would cause the distribution change of the magnetic induction intensities,which can be monitored in real-time by the magnetometer no matter in the static states or dynamic bending motions.Besides horizontal migration,occurrences of intervertebral subsidence in the vertical plane of the vertebrae can also be effectively distinguished based on the obtained characteristic variations of magnetic induction intensities.This strategy exemplifies the potential of superparamagnetic Fe_(3)O_(4) particles in equipping 3D-printed orthopedic implants with wireless monitoring capabilities,holding promise for aiding patients'rehabilitation.

Compatible hybrid 3D printing of metal and nonmetal inks for direct manufacture of end functional devices

The currently available 3D printing still cannot simultaneously deal with the metal and nonmetal inks together due to their huge difference in the melting points and poor compatible printability between each other. Here through introducing the low melting point alloy Bi35In48.6Sn16Zno.4 and silicone rubber as functional inks, we proposed a compatible hybrid 3D printing method for manufacturing the desired device, the supporting substrate and the allied package structure together. The principle of pneumatic-typed 3D printing of multiple inks was described and typical physical properties of the ink Bi35In48.6Sn16Zno.4 were measured. Several key factors dominating the printing quality such as the temperature of the printing head, the air pressure exerted upon the liquid metal ink in the syringe, the moving velocity and the height of the printing head etc. were clarified. A general way of directly printing out 3D structured electronic devices consisting of both metal and nonmetal materials was demonstrated. Such hybrid objects were patterned and formed up layer by layer with Bi35In48.6Sn16Zno.4 alloy and silicone rub- ber which would become solidified after standing for a period of time under room temperature. To illustrate the compatible printability of these printing inks, a three-layer tricolor LED stereo circuit with controlled lighting capability was further man- ufactured and evaluated. The present study opens an important hybrid 3D printing way for directly manufacturing functional and structural end devices in an easy and low cost way.

Application of 3D Printing and WebGL-Based 3D Visualisation Technology in Imaging Teaching of Ankle Joints

With the rapid development of medical technology,3D printing technology with realistic representation can perfectly display static human anatomy,while 3D visualisation technology based on Web Graphics Library(WebGL)can promote the rigid replication characteristics of traditional teaching models and express the dynamic spatial relationship between different anatomical structures.Medical students traditionally have less cognition of ankle ligament sprains.In this study,computed tomography(CT)and magnetic resonance imaging(MRI)data of the ankle joints of volunteers were used to print models of the ankle bone,tendon,and ligament using 3D printing technology,and a real-time interactive 3D digital model of the functional ankle joint was designed using 3D visualisation based on WebGL and 2D image real-time rendering technology for interactive teaching.The utility of the 3D printing model combined with the WebGL-based 3D digital teaching model was evaluated in comparison with traditional teaching methods in 24 medical students.The results showed that the total score of students in the experimental group(mean±SD,79.48±12.93)was significantly better than that of the control group(61.00±14.94)with P<0.05.The practical test scores of the experimental group(18.00±2.70)were significantly higher than those of the control group(13.67±4.96)with P<0.05.In the satisfaction survey,the feedback questionnaire showed that the interactive teaching model of 3D printing technology combined with WebGL-based 3D visualisation technology was recognised by students in terms of quality and overall satisfaction.In addition,female students who used 3D printing combined with WebGL-based 3D visualisation technology as learning aids had a greater difference in practical test scores from the control group than male students.This study has demonstrated that the interactive teaching mode of 3D printing combined with WebGL-based 3D visualisation technology is beneficial to the teaching of medical imaging,enriching the learning experience of students,and increasing the interaction between teachers and students.

Studies on the cytocompatibility,mechanical and antimicrobial properties of 3D printed poly(methyl methacrylate)beads

Osteomyelitis is typically a bacterial infection(usually from Staphylococcus)or,more rarely,a fungal infection of the bone.It can occur in any bone in the body,but it most often affects the long bones(leg and arm),vertebral(spine),and bones of the foot.Microbial success in osteomyelitis is due to their ability to form biofilms which inhibit the wound healing process and increases resistance to anti-infective agents.Also,biofilms do not allow easy penetration of antibiotics into their matrix making clinical treatment a challenge.The development of local antibiotic delivery systems that deliver high concentrations of antibiotics to the affected site is an emerging area of research with great potential.Standard treatment includes antibiotic therapy,either locally or systemically and refractory cases of osteomyelitis may lead to surgical intervention and a prolonged course of antibiotic treatment involving placement of antibiotic-doped beads or spacers within the wound site.There are disadvantages with this treatment modality including insufficient mixing of the antibiotic,lack of uniform bead size,resulting in lower antibiotic availability,and limitations on the antibiotics employed.Thus,a method is needed to address biofilm formations in the wound and on the surface of the surgical implants to prevent osteomyelitis.In this study,we show that all antibiotics studied were successfully doped into PMMA and antibiotic-doped 3D printed beads,disks,and filaments were easily printed.The growth inhibition capacity of the antibiotic-loaded PMMA 3D printed constructs was also demonstrated.

Frontiers of 3D Printing/Additive Manufacturing: from Human Organs to Aircraft Fabrication

It has been more than three decades since stereolithography began to emerge in various forms of additive manufacturing and 3D printing. Today these technologies are proliferating worldwide in various forms of advanced manufacturing. The largest segment of the 3D printing market today involves various polymer component fabrications, particularly complex structures not attainable by other manufacturing methods.Conventional printer head systems have also been adapted to selectively print various speciated human cells and special molecules in attempts to construct human organs, beginning with skin and various tissue patches. These efforts are discussed along with metal and alloy fabrication of a variety of implant and bone replacement components by creating powder layers, which are selectively melted into complex forms（such as foams and other open-cellular structures） using laser and electron beams directed by CAD software. Efforts to create a ＂living implant＂ by bone ingrowth and eventual vascularization within these implants will be discussed briefly. Novel printer heads for direct metal droplet deposition as in other 3D printing systems are briefly described since these concepts will allow for the eventual fabrication of very large and complex products, including automotive and aerospace structures and components.

In vivo analysis of post-joint-preserving surgery fracture of 3D-printed Ti-6Al-4V implant to treat bone cancer

Cancer growth in the bone due to its random shape disables bone strength and thus changes its capacity to support body weight or muscles,which can crucially affect the quality of human life in terms of normal walking or daily activities.For successful patient recovery,it is necessary to remove the cancer-affected minimal bone area and quickly replace it with a biocompatible metal implant within less than 2 weeks.An electron beam-melted Ti-6Al-4V implant was designed and applied in a patient to preserve the natural knee joint close to the bone tumor.The developed implant fits the bone defect well,and the independent ambulatory function of the natural knee joint was restored in the patient within six weeks after surgery.A delayed fracture occurred six months after the successful replacement of cancer-affected bone with Ti-6Al-4V implant at the proximal meshed junction of the implant because of a minor downward slip.Microstructural,mechanical,and computational analyses were conducted for the fractured area to find the main reason for the delayed fracture.Our findings pertaining to the mechanical and material investigation can help realize the safe implantation of the three-dimensionally printed titanium implant to preserve the natural joints of patients with massive bone defects of the extremities.

Application of 3D-printed prosthesis in revision surgery with large inflammatory pseudotumour and extensive bone defect: A case report

BACKGROUND Hip revision surgery is the final treatment option for the failure of artificial hip joints, but it is more difficult than the initial operation. For patients with hip joint loosening around the prosthesis combined with large inflammatory pseudotumours and large segment bone defects, hip revision is even more difficult, and clinical reports are rare.CASE SUMMARY Male, 59 years old. The patient underwent left hip replacement 35 years ago and was now admitted to hospital due to massive masses in the left thigh, shortening of the left lower extremity, and pain and lameness of the left hip joint. X-ray, computed tomography and magnetic resonance imaging revealed prosthesis loosening, left acetabular bone defect(Parprosky IIIB type), and a bone defect of the left proximal femur(Parprosky IIIA type). Inflammatory pseudotumours were seen in the left hip and left thigh. Hip revision surgery was performed using a 3Dprinted custom acetabular prosthesis was used for hip revision surgery, which was produced by Arcam Electron Beam Melting system with Electron Beam Melting technology. The operation was successful, and the patient was followed up regularly after the operation. The custom-made acetabular prosthesis was well matched, the inflammatory pseudotumour was completely removed, the postoperative hip prosthesis was stable, and the old greater trochanter fracture was well reduced and fixed. The patient was partially weight-bearing with crutches 3 mo after the operation and walked with full weight-bearing after 6 mo. The hip prosthesis was stable, and there was no recurrence of inflammatory pseudotumours at the last follow-up. The Visual Analogue Scale was 3, and the Harris hip score was 90.CONCLUSION The use of 3D-printed personalized custom prostheses for complex hip revision surgery has satisfactory surgical results and has great clinical application value.

A New Three-Dimensional(3D)Printing Prepress Algorithm for Simulation of Planned Surgery for Congenital Heart Disease

Background:Three-dimensional printing technology may become a key factor in transforming clinical practice and in significant improvement of treatment outcomes.The introduction of this technique into pediatric cardiac surgery will allow us to study features of the anatomy and spatial relations of a defect and to simulate the optimal surgical repair on a printed model in every individual case.Methods:We performed the prospective cohort study which included 29 children with congenital heart defects.The hearts and the great vessels were modeled and printed out.Measurements of the same cardiac areas were taken in the same planes and points at multislice computed tomography images(group 1)and on printed 3D models of the hearts(group 2).Pre-printing treatment of the multislice computed tomography data and 3D model preparation were performed according to a newly developed algorithm.Results:The measurements taken on the 3D-printed cardiac models and the tomographic images did not differ significantly,which allowed us to conclude that the models were highly accurate and informative.The new algorithm greatly simplifies and speeds up the preparation of a 3D model for printing,while maintaining high accuracy and level of detail.Conclusions:The 3D-printed models provide an accurate preoperative assessment of the anatomy of a defect in each case.The new algorithm has several important advantages over other available programs.They enable the development of customized preliminary plans for surgical repair of each specific complex congenital heart disease,predict possible issues,determine the optimal surgical tactics,and significantly improve surgical outcomes.