Ming Jie Tan co-found and assumed the role of Chief Scientific Officer at DeNova Sciences in 2014. He is passionate about bridging the Gaps in the personal care industry after the bans of animal testing for cosmetics by directing DeNova to provide alternative methods that are more accurate and high reproducibility. He is a serial entrepreneur that accepts challenges in a bid to transform them to business opportunities. He nurtures and creates an environment to encourage learning and personal growth. Learning is continuous and never-ending.  Ming Jie (MJ) will be participating in the virtual 3DHEALS/NAMIC 2020 Summit on September 18th.

Jenny: When was the first encounter you had with 3D printing? What was that experience like? What were you thinking at that moment?

MJ: The first encounter with 3D printer was during Cellink Demo in NUS where the hydrogel-based matrix is made into shape. As I have been creating artificial skin using collagen, I have the thoughts of using them to replace the making of artificial skin and adding more structure variance to it.

Jenny: What inspired you to start your journey in biofabrication?

MJ: The thoughts of creating more human resemblance skin and eventually different organs.

Jenny: Who inspired you the most along this journey in biofabrication?

MJ: The Ethos of the company – Replacing Animal Testing

Jenny: What motivates you the most for your work? 

MJ: When a clinician is excited about a 3D print and finds it helpful, that’s very motivating for me.

When you see the final product become more real and similar to the one I had in mind. The Step by Step improvement spurs you on.

Jenny: What is/are the biggest obstacle(s) in your line of work? If you have conquered them, what were your solutions? 

MJ: Biomaterial and engineering expertise, and of course funding. Collaborate and get hands-on.

NAMIC support is crucial in getting funding to kickstart prototype.

Jenny: What do you think is (are) the biggest challenge(s) in 3D Printing/bio-printing? What do you think the potential solution(s) is (are)?

MJ: Cost and Reproducibility for bioprinting. It’s the whole 3D bioprinting ecosystem where knowledge can be more readily shared.

Jenny: If you are granted three wishes by a higher being, what would they be? 

MJ: Granted fund for more R&D, having a knowledgeable AI Robot that know all question you posed to them and Time Reversal. HaHa!

Related Articles:

3D bioprinting for tissue regeneration: Implications for burns and beyond

Bio-printing Ethics and Regulation – Part I, The Good

Interview with Boyle Suwono, CTO of Structo, Singapore

Interview: Dr. Jing Jianlong, Dental 3D Printing, China

Influencer Interview: Dr. Raymond Wong, Singapore

Interview: Dr. Chaw Sing Ho, Co-Founding Managing Director of NAMIC

Interview: Mahendran V Reddy, Singapore

3D Med 19 Conference (Australia) Recap

Interview: Dr. Chen Ching Kit, Pediatric Cardiac 3D Printing, Singapore

3D Printing Coaxial Nozzles Enabling Rapid Fabrication of Biofunctional Hydrogel Conduits

Interview with Dr. Jing Lim, CTO Osteopore, Singapore

Control your 3D Bioprinting Hydrogels

The post Interview with Ming Jie Tan, CSO, DeNova Sciences, Artificial (Asian) Skin appeared first on 3DHeals.

Jordan Miller is an Assistant Professor of Bioengineering at Rice University and Co-Founder of Volumetric, a Houston-based startup focused on next-generation biomaterials and biofabrication technologies. Miller received his bachelor’s degree in Biology from MIT in 2003 and earned his Ph.D. in Bioengineering from Rice University in 2008. His primary interests combine synthetic chemistry, 3D printing, microfabrication, and molecular imaging to direct cultured human cells to form more complex organizations of living vessels and tissues for research in regenerative medicine. Precisely engineered in vitro systems at the molecular, micro- and meso-scale are well suited to decouple the relationship between tissue architecture and cell function. These systems are now permitting comprehensive closed-loop design and optimization of large-scale engineered tissues through refinement with computer models of mass transport and assessment of their therapeutic potential in vivo. Dr. Miller will be speaking at the upcoming 3DHEALS2020.

Jenny: What inspired you to start your career in bio-fabrication?

Dr. Miller: My first love in school was Biology, and I worked in all kinds of research labs to try to figure out what I wanted to focus on — ophthalmology research at Cedars-Sinai, fluid dynamics of fish swimming at MIT, and viral pathogenesis at Harvard Medical School. As an undergrad at MIT, I saw an intriguing talk by Professor Ioannis Yannas on how he was able to take collagen from cow skin and process it into a skin substitute for human patients with major burns over their body. The natural response to large area skin burns is the formation of scar (if you are lucky enough to survive the injury and can get enough graft material).

Professor Yannas’ work showed that his skin substitute could not only provide a near-limitless supply of skin substitute for human patients, but his engineered collagens completely prevented scar formation to dramatically improve the lives of burn victims. I was completely captivated; I approached him after the talk and asked if I could join his lab. I worked with him for two years in the Department of Mechanical Engineering and completed a small undergraduate thesis project on some of the pathophysiologies of scar tissue formation in response to injury. I was completely hooked on this idea of biofabrication — making novel materials and structures in the lab that can seamlessly integrate with the body and replace damaged tissues simply by encouraging resident cells to take a regenerative, rather than a reactive, response to the injury at hand. I’ve remained enamored with this idea ever since, and have built my career on this pursuit.

Jenny: How did you first encounter bioprinting? What was that experience like? What were you thinking at that moment?

Dr. Miller:

During my Bioengineering Ph.D. at Rice University, I learned about hydrogels — water-swollen polymer networks that closely matched the mechanics and water content of human tissue. The fact that they can be photopolymerized — converted from liquid to solid simply by shining the right color of light at the right intensity — I knew I wanted to study that phenomenon for my doctoral work. Our field was recognizing that the adage of “genotype leads to phenotype” — a cell’s genetic makeup leads to the cell’s behavior — is not a constant, but that cells are continuously sampling their surrounding environment or “microenvironment” and responding based on what they are able to sense. So, using my experience with confocal microscopy, we were the first group to utilize multiphoton polymerization to structure and pattern hydrogels containing living cells. It was an extremely powerful and high-precision technique, but I realized it wouldn’t have the fabrication throughput to build entire human organ replacements. So, I began looking to develop simpler techniques that were radically lower in cost, much higher in throughput and could work within the short timescales needed to keep human cells alive.

Jenny: What motivates you the most for your work?

Dr. Miller: The fact that we have a national organ donation waitlist whose prospects continue to worsen has been a major motivator for my life. When I was 16 and went to get my driver’s license in California, I had to answer the question “do you wish to register to be an organ and tissue donor?” This one question changed my entire outlook. The realization that more than 100,000 sick people are waiting, often for someone else to die, so that they can receive an organ donation to live was shocking and transformative to my young mind. I described this in more detail in a TEDx talk in 2012, and it remains a constant drive in my life.

A more recent review paper highlights that if a ready supply of replacement organs was available, it could not only clear the 100,000 people on the organ donation waitlist, but millions of people worldwide that are not currently sick enough or able to qualify to be on that list, yet could medically benefit from an organ transplant, could be treated. The technologies we are developing have a real potential to extend human life expectancy worldwide.

Jenny: What are the biggest challenges in your current work? What are the potential solutions?

Dr. Miller: I laid out many of the biggest challenges in a recent open-access perspective article, and they still remain. One of the biggest challenges we have been focusing on is how to make a complete blood vessel network to keep millions, and eventually billions, of human cells alive. It’s akin to the challenge of designing a city for people to live in: we must architect discrete regions where the residents can live, but we also must build the fluid conduits — roadways for cities and blood vessels for living human tissue — that can be used to deliver nutrients and remove waste. We have invented advanced 3D printing approaches to address this challenge and are now able to make large scale tissue constructs for the first time.

Jenny: What do you think are the biggest challenges facing the bio-printing industry? What do you think the potential solution(s) is (are)?

Dr. Miller: 3D printing of plastics is already having a tremendous impact on the medical space — everything from custom braces for broken bones, prosthetic devices, medical implants, and anatomical models to help with surgical planning.

For Bioprinting, which is more in its infancy, the challenges are finding the right way to bring the technology to market given that human clinical trials are probably still at least 5-10 years away. No one is doing large animal studies with whole organ bioprinting yet, because that large yet intricate structure simply cannot be built just yet. However, I believe the technology we and others are developing are now at the maturity where most of the research is done. We are more at the development stage, pushing current technologies to larger tissue volumes, with higher speed, and higher precision than was possible just 5 years ago.

We have to find the right cell sources that can be seeded into these tissue constructs or entrapped directly, but a lot of people working with iPS cells are doing just that. Finally, the prospect of building 3D printed tissues with human cells has a unique opportunity to engage with regulatory bodies such as the Food and Drug Administration (FDA) that will ultimately oversee and ensure the safety of human recipients.

Jenny: If you are granted three wishes by a higher being, what would they be? 

Dr. Miller:

An end to disease and suffering. Achieving the full potential of each individual, and indeed all of humanity is held back by biological and social issues that if obviated would bring about a dramatic acceleration of our collective progress. Volumetric’s technology is most directly applicable to this goal.

Plentiful and low-cost of clean energy. Access to energy will further underlie humanity’s access to education, healthcare, and quality of life. And clean energy may provide for such progress without a heavy toll on the worldwide ecosystem.

Interplanetary travel for humans. Exciting progress is being worked on in this space right now!

Jenny: What advice would you give to a smart driven college student in the “real world”? What bad advice did you hear that they should ignore?

Dr. Miller: I often share with trainees the wisdom of Professor Bob Langer: the single most important subjects to study are the fundamentals of your chosen major. If you become deeply specialized too early, it not only limits your future career options, it also can limit your ability to think critically and solve problems creatively or efficiently. For these reasons, I believe that often complained-about “breadth” classes are just as important as “depth” classes in college, as well as at later stages of education like graduate school. Even if you are a senior executive in a highly specialized field, it’s still important to keep up to date on what’s happening in other fields because their approach to problem-solving may help you break through your own perceived roadblocks.

Jenny: If you could have a giant billboard to promote a message to millions and even billions of people in our community (i.e. 3DHEALS community), what message would that be?

Dr. Miller: Register to become an organ donor today. 3D bioprinted organ replacements are still 5-10 years away from a first-in-human safety study, and there are more than 100,000 people in need right now. Checking one little box can positively impact the lives of up to eight other people in need.

Jenny: What were/was the best investment you made in 3D printing/bio-printing/bio-fabrication?

Dr. Miller: Diving into the RepRap project back in 2009 was my single best investment of time and money. I learned all about the power of open-source hardware and software, and I engaged with a worldwide community of thinkers and tinkerers who were able to help us progress our work on 3D bioprinting. We continue to be actively engaged with the worldwide open-source community, and this ethos is even permeating back into basic Science with the so-called “Open-Science” movement. The term “Open-Science” should be redundant… Science is supposed to be open! It’s very exciting to see the scientific community embracing this area and making their data available for others to review.

Jenny: What were/was the worst investment you made in 3D bio-printing/bio-fabrication?

Dr. Miller: We have generally steered away from what I would consider poor investments in this space – we buy open technology platforms, not appliances. The field is way too new for closed systems to provide the fuel we need to progress the field. Volumetric is listening to user feedback, and we have open-sourced our software platform to help provide for the future of this amazing field.

Jenny: What was/is the biggest risk you took in your career?

Dr. Miller: Moving from Biology to Bioengineering was a big risk for me at the time, not many people make that jump successfully. But I believed in myself and followed my interests and passions, and I remain captivated each and every day by the power of applying engineering principles to solving some of the biggest challenges in Biology and Medicine today.

Jenny: What do you enjoy in your spare time? What are you passionate about outside of your work/3d printing?

Dr. Miller: 3D printing! Designing and visualizing new blood vessel structures is actually a hobby of mine, and 3D rendering and animation with the open-source program Blender have helped us to communicate our work to a much larger audience. I also enjoy the outdoors — hiking, swimming, exploring so much of what Nature has to offer.

Jenny: What is your favorite quote? Why?

Dr. Miller: “The best way to predict the future is to invent it” — Alan Kay. This quote says to me that there’s no point in sitting back in an armchair and trying to be a prognosticator. It’s much more effective to actually work at the cutting edge of technology and become a driver for the future of humanity through personal effort and innovation. Teams working together towards a shared vision can do this even more effectively. I’ve been lucky enough to participate in several widely regarded innovations in my career thus far, and it’s been extremely gratifying to see our hard work extrapolated into new futures that couldn’t be imagined before, but now we and others believe are within our grasp.

Jenny: What does the word “3DHEALS” mean to you?  =)

Dr. Miller: The human body contains the most complicated structures in the known universe. These structures, such as the intricate three-dimensional blood vessel networks of the body, critically underlie human physiology. I see 3DHEALS as a summary that the best way to heal the human body is to better understand this 3D architecture and replicate it in a laboratory and, eventually, a clinical setting. If we can make replacement organs for people, made from their own cells, we can treat literally millions of people worldwide and extend overall human life expectancy. 3DHEALS will move the current medical paradigm of “one size fits all” to a highly personalized experience of precision medicine where “one size fits one”.

Related Articles:

Believe in Your Science: Interview with Dr. Orquidea (Orchid) Garcia, Johnson & Johnson

Bioprint A Heart: Interview with Fluidform3D CEO Mike Graffeo

The Heart of the Matter: Interview with Dr. Shafkat Anwar, UCSF

A Call to the Heart-A Perspective on the State of 3D Bioprinting of Cardiac Tissue

Cardiac 3D Printing: The Heart of the Matter

Interview: Jon Rowley, Founder & Chief Product Officer, RoosterBio

Cancer: What 3D Printing (Bioprinting) Can do For Oncological Care

The post Engineering Vasculatures: Interview w/ Dr. Jordan Miller appeared first on 3DHeals.

Australia’s largest 3D technologies in medicine conference were back for its 5^th consecutive year this year held on the 14-16^th November, at AAMI Park. This year’s conference boasted its largest and best-ever program that would delve deep into the topics of 3D printing, 3D modeling and segmentation, AR/VR, MedTech innovation, ethics and governance, and for the first time a bioprinting session. 

Dr. Jasamine Coles-Black the scientific convener and organizer of 3D Med alongside Dr. Jason Chuen the director of 3D Med Lab at Austin Health and The University of Melbourne organized a fantastic, engaging and cross-disciplinary event that encouraged strong collaboration and open-minded discussion about the positive outcomes that 3D technologies can have on shaping the future of patient care. 3D Med Lab’s goal is to explore the clinical applications of these new technologies targeting areas such as medical and healthcare professional education, patient education, procedural training and simulation, surgical pre-planning, medical devices, implants and prosthesis development all whilst understanding the important social and legal implications these technologies can have on society. 

Leading up to the conference, the newly established Australian Research Council’s Centre for Medical Implant Technologies or ARC-CMIT has been a culmination of great strides made in this space in recent years. This center brings together 24 organizations across hospital clinicians, academics, and industry in order to develop an integrated framework for 3D printed prosthesis, implants and personalized surgical devices including The University of Melbourne, Epworth Healthcare, Flinders University, and Griffith University. The 3D Med Lab team is proud to have been a key partner of this application from its inception and will be delivering key grass-roots clinical components of this center, facilitating industry, academics and engineers to gain experience in and understanding how these technologies will function in a real-life, working hospital environment.

Day One

The 3-day event kicked off with an anatomical modeling workshop hosted by Evok3D and Materialise. The workshop took participants through the medical image to 3D printing workflow, providing an overview of the segmentation, modeling and 3D printing process from start to finish. This was followed by an exciting workshop hosted by Stratasys and Fusetec unveiling the Australian launch of the Stratasys J750^TM Digital Anatomy^TM  3D printer. It showcased a new modern approach to training and perfecting surgical skills using 3D printed human anatomy with both standard and complex pathologies to allow physicians and medical students to hone their skills before entering the operating room. This workshop provided a great opportunity for a multidisciplinary discussion on the current possibilities and directions of 3D printing in procedural simulation and its potential in clinical and education applications. Back by popular demand after its success last year, the VR buffet tour offered an interactive experience of the SBS Digital Learning Hub (formerly the VRLS) at The University of Melbourne alongside a tour of the NExT Lab (a technology-focused maker space at the Melbourne School of Design). Next up was a tour of BioFab3D, Australia’s first robotics and biomedical engineering center where guests where offered the chance to see a variety of bioprinters in action and surgical robots on display. RMIT’s Centre for Additive Manufacturing hosted a tour of their huge 3D printing and additive manufacturing space, home to some seriously impressive equipment. Finally, the day concluded with the Women In 3D Technologies Networking Drinks event hosted by the CSIRO.

Day Two

The day began with an opening presentation from Professor Guy Maddern of the Royal Australasian College of Surgeons expressing the need for further understanding of the benefits vs the risks of 3D printing for personalized patient care. Detailing the lack of high-quality comparative evidence (majority single-arm studies), minimal safety data and quality economic analysis so we can confer the benefits that are promised by this technology to balance expenses with a health system under enormous pressure. Frank McGuire MP, The Parliamentary Secretary for Medical Research in Australia opens by saying that conferences like these are a great opportunity to celebrate leadership, excellence, and collaboration and that the Victoria government believes that constancy of purpose is really important, so you know who to talk to with the continuity to get things done!

Dr. Jason Chuen the Director of 3D Med Lab delivers a broad-ranging talk on how constant innovation of disruptive technologies presents barriers and challenges that need overcoming. Emphasizing that we now live in an age where patients deserve to have more of a say in how their care is conducted and that we must be open to new sources of information with a balance of experience. Driving change in the market stems from projects like the Aikenhead Centre for Medical Discovery (ACMD) that support innovation by more than a physical location but the ecosystem it creates.

With an abundance of great talks over the duration of the conferences, highlights from a few sessions include the presurgical planning talks by Dr. Joseph Ischia discussing 3D Visualization in Complex Urooncological Surgery and Dr. Felix Sim on 3D Printing Craniofacial Implants. The cardiovascular session saw Dr. Carmine Gentile discuss how his lab utilizes cardiac spheroids as building blocks for different approaches to improve tissue functionalization by microcapillary generation via VEGF addition to promote tissue fusion by intraluminal formation. Utilizing bioprinting techniques we can create more functional 3D structures with tailorable hydrogels allowing for deposition in specific confined locations, giving rise to enhanced spheroid interactions. Emphasizing the effectiveness of co-culturing techniques and the role that fibroblasts play in tissue maturation in determining structure-function hierarchy and subsequent contractile function. The Cardiovascular session finished with a brilliant presentation from the conferences organizer Dr. Jasamine Coles-Black discussing techniques and approaches to produce physician modified stent grafts. The visualization session held presentations from Dr. Michelle Rank in Bending the Knee: Can VR Rule Clinical Training Paradigms? and Andrew Hardidge with a fantastic presentation on 3D Printed Acetabular Models for Prosthesis Sizing. 

The last session for the day was focused on innovation and industry, a great keynote from Dr. David Ackland on the power that simulation tools have engineering the human jaw joint. Richard Stratton took to the stage to share a patient’s perspective on being the first Australian to receive a 3D printed jaw. Two 3D printed parts were screwed on to the bone to form the missing ball and socket joint. The research team’s leader, OMX Solutions founder and Epworth oral and maxillofacial surgeon Dr. George Dimitroulis, said that Melbourne-made prostheses could help many people around the world and that “we’re at the crossroads of an exciting era, where an increased use of 3D technologies will see customized medical devices become an integral part of healthcare”. This case highlights the talents and capabilities we have here in Australia to design, develop and manufacture our own high-tech medical devices. 

Day Three

Day 3 begins with some excellent 3-minute presentations in an opening quick shot session followed by great plenary talk by Prof. Mia Woodruff on the origins and utilization of biomaterials, future directions with bioprinting applications, developments of low-cost 3D scanning techniques for microtia using iPhones and an update on the progression of the Herston Biofabrication Institute at the Metro-North Hospital due to open next year. 

Next up, Dr. Claudia di Bella gave her thoughts on a surgeon’s perspective to 3D bioprinting technologies followed by an inspiring talk by Dr. Tegan Cheng on the work of the EPIC lab at Westmead Children’s Hospital is doing with designing and developing personalized medical devices for children. 

The ethics and governance session saw Dr. Cathal O’Connell give a talk titled Don’t Print Your Heart Out: The Dangers of Sensationalism in Science. Reiterating that science journalism is a dying perfection with fewer dedicated scientific reporting roles and without coordination from university PR departments, media journalists sometimes engage in sensationalism and exaggeration from the original journal article. What’s wrong with a bit of hype? Does the enthusiastic portrayal of 3D printing technologies have ethical side effects in terms of a patient’s perception and consent? Much like many disruptive technologies, we see cycles of hype and excitement followed by periods of stagnant progression due to cuts in funding and lack of deliverable outcomes from the promise that technology holds. Everybody is complicit and shares the responsibility of how our research is recorded in media and communicated with the general public – and particularly as academics we often ride the wave of hype in order to secure funding – yet it’s important not to get caught up in your own hype otherwise there are implications. For the last session of the conference, the topic was validation and Nathaniel McTaggart discussed the process of starting a 3D printing service at Auckland City Hospital whilst Dr. Stewart Ryan conveyed the use of 3D printing for veterinary education and surgical planning. 

As a first-time attendee, this conference really stood out to me from the diversity of talks from clinicians, academics and industry but with important input and engaging panel discussions from government representatives from the Department of Health and Human Services on the medical research sector and the Therapeutic Goods Administration (TGA) on regulatory reforms to personalized medical devices. I’d like to thank everyone involved with putting together such an amazing event and already looking forward to the next.

About the Author:

William Harley graduated with honors in medical biotechnology from the University of New South Wales. Currently, he is undertaking a Ph.D. at the University of Melbourne in acoustophoretic bioprinting. Stemming from his research experience in biomaterials, stem cells, and nanofabrication, he is driven by the clinical translation of personalized regenerative medicine. He is passionate about the innovation of 3D printing in healthcare and is determined to orchestrate a series of 3D HEALS events to engage in the Australian community.

Related Articles:

Bioprinting Down Under (Australia): Recent Workshop Take-away

Interview: Jason Chuen, Director of Vascular Surgery at Austin Heath, Australia

Interview: Dr. Paul D’Urso, Australian Neurosurgeon and the Founder & Executive Chairman of the Anatomics

3DHeals at Vancouver Island Health Sciences

The post 3D Med 19 Conference (Australia) Recap appeared first on 3DHeals.

Innovation in silos is dangerous. What’s equally unrealistic is to think that 3D printing will be the only force that will save the world. It will not. Often times, several technologies can work together to create something much more powerful. Several articles in this week’s selection demonstrated the merge of robotics and 3D printing technologies, with various application. One particular fun read was from an Italian group that created a self-growing obstacle avoiding robot that also simultaneous acts as a 3D-printer, enabling a tree-root like growth through an artificial pathway. What healthcare application can you think with that technology? Relating to my recent visit to the Cleveland Clinic, autonomous robotic surgery may not be as far as you can imagine. Another equally intriguing paper was by an Isreali group focusing on decentralized mitigation of world pandemics. This paper has more math than perhaps we want, but it is a serious discussion on how 3D printing can be leveraged in solving public health issues. I have touched upon decentralized healthcare in the past from a different angle. 

“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.

Improvement of osseointegration by recruiting stem cells to titanium implants fabricated with 3D printing

Authored by Mary Bollman, Raphael Malbrue, Chunhong Li, Hong Yao, Shengmin Guo, Shaomian Yao. ANNALS of the New York Academy of Sciences. October 11 2019.

Immobilization of BMP-2-derived peptides on 3D-printed porous scaffolds for enhanced osteogenesis.

Authored by Xiashiyao Zhang, Qi Lou, Lili Wang, Shan Min, Meng Zaho, and Changyun Quan. Biomedical Materials. November 15 2019.

CT and MRI compatibility of flexible 3D printed materials for soft actuators and robots used in image-guided interventions.

Authored by Wiebke Neumann, Tim P. Pusch, Marius Siegfarth, Lothar R. Schad, Jan L. Stallkamp. Medical Physics. October 6 2019.

Passive Morphological Adaptation for Obstacle Avoidance in a Self-Growing Robot Produced by Additive Manufacturing

Authored by Ali Sadeghi, Emanuela Del Dottore, Alessio Mondini, and Barbara Mazzolai. Soft Robotics. February 6 2020.

Digitizable therapeutics for decentralized mitigation of global pandemics

Authored by Adar Hacohen, Reuven Cohen, Sol Efroni, Baruch barzel and Ido Bachelet. Nature Scientific Reports. October 4 2019.

The post From Academia: 3D Printing and Robotics, Stem cell coated Implants, Decentralized Mitigation of Pandemics appeared first on 3DHeals.

Want to write a piece for 3DHEALS Expert Corner? Email us: info@3dheals.com

3D Printed PU-based conduits with 3D engineered Schwann cell blocks for enhancing the peripheral nerve regeneration

The nervous system is part of our body and plays a key role in coordinating action and sensory information as well as communicating between different body parts through the electrical signal transmission. The system works by coordinating inputs from different sources and transforming them into actions and autonomous outputs that respond to environmental changes. Therefore, severe neurological dysfunction or injury can lead to disability and have a significant negative impact on the quality of life of patients [1]. The human nervous system can be identified as two subsystems, one is the central nervous system (CNS) and the other is the peripheral nervous system (PNS). The CNS includes the brain and spinal cord, while the PNS contains other nerve tissues besides the brain and spinal cord [2]. Patients involved in major trauma often suffer from peripheral nerve damage due to the extent of the impact, and such injuries typically include nerve compression, nerve damage or tearing or even ischemic injury. Other causes of peripheral nerve injury include surgery and other complications. These damages can then lead to a variety of neurological dysfunctions and diseases. In addition, studies have shown that approximately 2.8% of patients still claim peripheral neuropathy after treatment, some have neuropathic pain and permanent dysfunction, and some patients have a permanent disability even after years of recovery [3]. With the advancement of medical technology and knowledge, the success rate of peripheral nerve therapy has increased significantly. However, due to the limited regenerative capacity of the nerves, there is still a huge gap between the upon solutions and the complete recovery of neurological function. To date, the inclusion of regenerative medicine in peripheral nerve therapy remains challenges [4] due to major obstacles including lengthy duration of regeneration, limited neuronal sources of autografting, and autologous transplant rejection. Therefore, scientists are always looking for new solutions to overcome these challenges. Tissue engineering has long been regarded as a potential replacement for nerve transplantation since the past decade, and it has become an important research topic in the field of nerve regeneration [5].

Attempting to regenerate or replace severe nerve damage is a major challenge nowadays. Temporary loss of neurological function after any nerve injury is unavoidable due to the disruption of communication between nerves. Previous cases have shown that patients who underwent >15 mm neurological repair often claimed loss of function even after recovery. In addition, nerve damage involving > 15 mm distance may significantly reduce nerve regeneration due to the disruption of internal nerve contact between the proximal and distal ends [3]. Clinically, autologous nerve grafting is currently the mainstream treatment for nerve damage. Neural grafts from autologous sources are optimal because they are not only proven to protect damaged nerve tissue, but also help guide axonal regeneration and connect to one nerve ending to another. In recent years, it has been suggested that 3d porous scaffolds only provide temporary support for cell growth in cells [6]. However, modern stents have evolved into a key factor in tissue engineering applications, and these stents have proven to be more than just containers or supports [7]. Therefore, they are also rich in growth factors, which can significantly promote nerve regeneration [8]. Among them, Zhang conducted a 20-year study involving peripheral nerve defects, and the data collected were used to establish research guidelines for peripheral nerve conduits [9]. Studies have shown that neuropathy with a size of 9.7 ± 1.8 mm can be successfully regenerated by the use of a nerve conduit. However, for the repair of rat sciatic nerves greater than 10 mm, several different proteins such as laminin [10], fibronectin [11] and collagen [12] need to be incorporated into the nerve conduit to achieve optimal nerves regeneration.

China Medical University (CMU) adapted the advancement of additive manufacturing technology to fabricate innovative nerve conduits with complex pore patterns and dimensions with high precision. We used Digital light processing (DLP), a photo-polymerization technique to cross-link photo-curable materials, to fabricate nerve conduits. This printed nerve conduit will present as a scaffold for two reasons in this research, one is to hold/contain the decellularized extracellular matrix (dECM) of nerves and the other is to exist as a scaffold for nerve regeneration from the damaged nerve ends. The dECM was usually obtained by exposing harvested nerves with chemical or physical methods to remove unnecessary cellular components, thus only maintaining the structural proteins and several growth factors that were supposed to mimic the microenvironment of normal tissues. In the CMU 3D Printing group, we fabricate water-based light-cured polyurethane (PU) nerve conduits with DLP technology. To improve the resolution and biocompatibility of PU, homogenous polydopamine (PDA) and dECM were mixed into the raw material. Mechanical properties and chemical composition were analyzed using the EZ test and electron spectroscopy for chemical analysis (ESCA). In general, PU/PDA/dECM conduits (Figure 1) were able to influence and enhance stem cell adhesion, proliferation and neural differentiation of stem cells.

Furthermore, our group also adopted an updated method to manufacture the three-dimensional cell-containing blocks, as Figure 2. This innovative 3D cell-containing blocks achieved several advantages including first, being able to be efficiently expanded to achieve rapid production; secondly, having standardized size in order to prevent them from blocking or destroying the nozzle during their processing or passing through the nozzle of the bioprinter; thirdly, manufacturing methods thereof not able to induce significant cell damage and/or gene (DNA) damage; and fourthly, manufacturing methods thereof not able to impair its ability to integrate into tissues. In nerve regeneration, we used the microRNA-transfected Schwann cells (SC) to fabricate the SC blocks and loaded SC blocks into the nerve conduit to enhance nerve regeneration rate. Signal-channel neural conduits with SC blocks were implanted into Sprague-Dawley rats [Figure 3 and 4] and observe the SC blocks will secrete more nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). In an animal in vivo study, there was no foreign body membrane formed around the nerve conduit and could be incorporated with natural growth factors for optimal biocompatibility in regenerative nerve tissue engineering.

References:

1. Cheney, F. W.; Domino, K.; Caplan, R. A.; Posner, K. L. Nerve injury associated with anesthesia. Anesthesiology 1990, 90, 1062–1069.

2. Kouyoumdjian, J. A. Peripheral nerve injuries: A retrospective survey of 456 cases. Muscle & Nerve 2006, 34, 785–788.

3. Tajdaran, K.; Gordon, T.; Wood, M. D.; Shoichet, M. S.; Borschel, G. H. A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts. Acta Biomater 2016, 29, 62–70.

4. Johnson, B. N.; Lancaster, K. Z.; Zhen, G.; He, J.; Gupta, M. K.; Kong, Y. L.; Engel, E. A.; Krick, K. D.; Ju, A.; Meng, F.; Enquist, L. W.; Jia, X.; McAlpine, M. C. 3D printed anatomical nerve regeneration pathways. Adv Funct Mater 2015, 25, 6205–6217.

5. Xia, B.; Lv, Y. Dual-delivery of VEGF and NGF by emulsion electrospun nanofibrous scaffold for peripheral nerve regeneration. Mater Sci Eng C Mater Biol Appl 2018, 82, 253–264.

6. Maiti, B.; Díaz Díaz, D. 3D printed polymeric hydrogels for nerve regeneration. Polymers 2018, 10, 1041

7. Kankala, R. K.; Xu, X. M.; Liu, C. G.; Chen, A. Z.; Wang, S. B. 3D-printing of microfibrous porous scaffolds based on hybrid approaches for bone tissue engineering. Polymers 2018, 10, 807.

8. Jubran, M.; Widenfalk, J. Repair of peripheral nerve transections with fibrin sealant containing neurotrophic factors. Exp Neurol 2003, 181, 204–212.

9. Ko, C. H.; Shie, M. Y.; Lin, J. H.; Chen, Y. W.; Yao, C. H.; Chen, Y. S. Biodegradable bisvinyl sulfonemethyl-crosslinked gelatin conduit promotes regeneration after peripheral nerve injury in adult rats. Sci Rep 2017, 7, 1062.

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About the Author:

Dr. YiWen Chen received her M.S. and Ph.D. degrees in Industrial and Manufacturing Engineering (Nanomaterial Group) Florida State University, USA. She joined China Medical University Hospital and funded the 3D Printing Medical Research Center in 2014. She is responsible for leading the team and developing and implementing the 3D printed medical research and clinical application integration. She is also the Associate Professor of Graduate Institute of Biomedical Science at China Medical University since then. Dr. Chen’s research interests focus on to develop and deliver advanced and affordable 3D printed medical care including biomedical devices, implants, and therapeutics for medical applications. Several of her patents and technologies have to tech-transfer to industries. She was awarded the 2017 and 2018 Innovation in Taiwan. She is also a member of the Board of Supervisors of the Additive Manufacturing Association in Taiwan(AMAT) and a board of directors of China Medical Derivatives Corporation – Everyoung Biomedical International. She is responsible for providing relevant technical advice and is often invited to serve as lecturers at many international academic conferences. Many achievements of her research team are also recognized by high-impact journals, media, conference scientific publications, and published works. She has published 35 peer-reviewed articles and holds 15 issued/pending patents.

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Polymer and biopolymer derived hydrogels are ideal for replicating human tissue (the extracellular matrix of which is itself a hydrogel).

The fabrication and reproduction of human tissue for medical training and diagnostic purposes is a costly but critical component of quality healthcare. Tubular constructs represent a common type of structure in human anatomy and include renal, vascular, pulmonary, and gastrointestinal tissues. Tubular constructs are geometrically simple, but the fabrication of these structures is still a challenge. Synthetic vessels—composed of biological hydrogels such as collagen—are currently fabricated by casting or rolling a polymeric material around a mandrel, wherein the diameter of this mandrel dictates the size of the lumen. This approach can yield tubular constructs with biological and mechanical properties that are comparable to human blood vessels. However, these approaches are challenged by the cost, as well as the fabrication of small lumen diameters (<1 mm) and arbitrary length tubes (>10 mm).

We recently reported a methodology (in collaboration with the Theberge laboratory at the University of Washington) to fabricate hydrogel-based tubular conduits based on the extrusion of shear-thinning hydrogels from a customizable 3D printed coaxial nozzle.

Different nozzle geometries can be modeled via computer-aided design (CAD) and 3D printed in order to generate tubes or coaxial filaments with different cross-sectional geometries. We were able to fabricate tubes with luminal diameters or wall thicknesses as small as ~ 150 µm. Moreover, these tubes can be functionalized with collagen I to enable cell adhesion, and human umbilical vein endothelial cells (HUVECs) can be cultured on the luminal surfaces of these tubes to yield tubular endothelial monolayers. Our approach enables the rapid fabrication of biofunctional hydrogel conduits which can ultimately be utilized for engineering in vitro models of tubular biological structures, such as blood vessels.

This is just one example that demonstrates how 3D printing is poised to change how we think about research and products of the future. Coaxial nozzles, such as the one we designed, can be rapidly designed and produced via SLA printing within a manner of hours. Without a 3D printer in house, a materials laboratory like ours could not have produced such nozzles without a significant amount of time and investment into machining and assembling individual parts. We hope to make our own designs widely available. Thus, in the spirit of the openness of the 3D printing community, the STEP and STL files of our nozzles are available for those interested in printing their own.

About the Nelson Laboratory: The Nelson laboratory develops stimuli-responsive materials and bio-hybrid materials that are compatible with additive manufacturing (AM) processes. They particularly focus on developing materials for AM that can impact applications in the life sciences.

Reference:

3D printed coaxial nozzles for the extrusion of hydrogel tubes toward modeling vascular endothelium

About the Author:

Alshakim Nelson is an Assistant Professor in the Department of Chemistry at the University of Washington. He received his Ph.D. in organic chemistry from the University of California, Los Angeles in 2004, where he worked with Sir J. Fraser Stoddart on carbohydrate-containing polymers and macrocycles. He was then an NIH postdoctoral fellow at the California Institute of Technology working for Professor Robert Grubbs on olefin metathesis catalysts for the formation of supramolecular ensembles. Dr. Nelson joined IBM Almaden Research Center in 2005 as a Research Staff Member where he focused on the synthesis of nanomaterial building blocks that enabled large area nanomanufacturing via self-assembly. In 2015, Dr. Nelson joined the faculty at the UW, where his research group focuses on the synthesis, characterization, and processing of stimuli-responsive hydrogels for 3D printing. Dr. Nelson has over 40 publications and 11 issued patents. His honors and awards include recognition as an IBM Master Inventor, ACS PMSE Young Investigator, Kavli Foundation Fellow, NSF CAREER award, and 3M Non-Tenured Faculty Award.

Author’s Representative Publications:

Wong, J.; Gong, A. T.; Defnet, P. A.; Meabe, L.; Beauchamp, B.; Sweet, R. M.; Sardon, H.; Cobb, C. L.; Nelson, A. 3D Printing ionogel auxetic frameworks for stretchable sensors. Adv. Mater. Technol. 2019, 4, 1900452.

Shafranek, R. T.; Leger, J. D.; Zhang, S.; Khalil, M.; Gu, X.; Nelson, A. Sticky ends in a self-assembling ABA triblock copolymer: the role of ureas in stimuli-responsive hydrogels. Mol. Sys. Des. Eng. 2019, 4, 91.

Fellin, C. R.; Adelmund, S. M.; Karis, D. G.; Shafranek, R. T.; Ono, R. J.; Martin, C. G.; Johnston, T. G.; DeForest, C. A.; Nelson, A. Tunable temperature- and shear-responsive hydrogels based on poly(alkyl glycidyl ether)s. Polym. Int. 2019, 68, 1238.

Saha, A.; Johnston, T. G.; Shafranek, R. T.; Goodman, C. J.; Zalatan, J. G.; Storti, D. W.; Ganter, M. A.; Nelson, A. Additive manufacturing of catalytically active living materials. ACS Appl. Mater. Interfaces 2018, 10, 13373.

Basu, A.; Saha, A.; Goodman, C.; Shafranek, R. T.; Nelson, A. Catalytically initiated gel-in-gel printing of composite hydrogels. ACS Appl. Mater. Interfaces 2017, 9, 40898.

Karis, D. G.; Ono, R. J.; Zhang, M.; Vora, A.; Storti, D.; Ganter, M. A.; Nelson, A. Cross-linkable multi-stimuli responsive hydrogel inks for direct-write 3D printing. Polym. Chem. 2017, 8, 4199.

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