regenHU CEO: Bioprinting Will Strengthen OrganTrans Project to 3D Print Liver Organoid

The European consortium OrganTrans is preparing to develop a tissue engineering platform capable of generating liver tissue. The proposed automated and standardized disruptive alternative solution to organ donation for patients with liver disease will stand on 3D bioprinting know-how from Swiss biomedical firm regenHU. Coordinated by Swiss research and development center CSEM, the eight partners and two transplantation centers engaged in the consortium will be using regenHU’s 3D bioprinters to produce organoid-based liver constructs with organoid laden bioinks.

In April 2020, we reported that OrganTrans would tackle the important healthcare challenge of end-stage liver disease (ESLD) by capitalizing on advancements in the regenerative medicine field, like using biofabricated liver tissue, to develop an entire value chain from the cell source to tissue engineering, biofabrication, post-processing and testing, and liver transplantation under the “compassionate use exemption” regulation (which provides an important pathway for patients with life-threatening conditions to gain access to unproven human cells and tissue products). To understand the key role of biofabrication in this innovative project, asked regenHU’s new CEO, Simon MacKenzie, to tell us more about the challenges that lie ahead for the European consortium and his company.

regenHU CEO Simon MacKenzie (Image courtesy of regenHU)

The project officially began in January 2020, what can we expect when it ends in December 2022?

The current goal of this project is to create a functional biofabricated liver construct that can be implanted into a mouse model. I consider that the OrganTrans team will accelerate new solutions for patients with liver failure. It is challenging, but we do envision successful in vivo trials. Of course, this major achievement will not be the end of the story; significant work and research will still be required to transfer these results to human clinical trials. The major remaining challenges will probably be the process scale-up to produce larger tissue and regulatory aspects.

Will this research be groundbreaking to treat liver disease in the future?

Demonstrating the feasibility of the approach in a mouse model will be groundbreaking for the disease because it will demonstrate its potential as an alternative to transplantation. Diseases like NASH [nonalcoholic steatohepatitis, an aggressive form of fatty liver disease] are increasing dramatically, and likely to be a leading cause of death within the next few years. Moreover, the difficulty of detecting the disease until it is potentially too late leads to significant challenges for therapeutic intervention, meaning transplantation will remain the main option for severely affected patients. This well-recognized need, along with the lack of donor organs will ensure bioprinted livers will continue to be well funded. But the value of the project goes beyond liver disease, as the new technologies developed in the frame of OrganTrans will not be limited to liver applications. They relate to the challenges of biofabrication of any organoid-based tissue, which can potentially be beneficial for a large variety of indications.

Can you tell me more about the role of regenHU within the OrganTrans consortium?

Such a complex and ambitious endeavor needs very different and complementary knowledge and competences. Teamwork will be a central element, first to enable, then to accelerate, these new solutions. With this in mind, we have been reorganizing regenHU to bring better project collaborative capabilities to this project, and others like it that we are engaged in. regenHU is a pioneer and global leader in tissue and organ printing technologies converging digital manufacturing, biomaterials, and biotechnology to lead transformational innovations in healthcare. We focus on delivering advancements in the instruments and software required for tissue engineering, and our technology evolving along with the biological research of our partners. We, therefore, consider these partnerships with the scientific community critical for our development.

An outline of the OrganTrans project (Image courtesy of OrganTrans)

regenHU is one of the largest contributors to this project, is this part of the company’s commitment to regenerative medicine?

We can see the need for biotechnology solutions for a wide range of disease states. Our strengths are in engineering the instruments and software necessary to allow the producers of biomaterials and the suppliers of cells to combine their products to achieve functional tissues and organs. Our commitment is to provide disruptive technologies that will enable the community to make regenerative medicine a reality, with precision and reproducibility in mind, for today’s researchers and tomorrow’s industrial biofabrication needs. One of the key challenges is the current limitation in the scale and volume of bioprinting which is linked to the reproducibility of the print. To progress into the manufacture of medical products, bioprinters will need to operate at a scale beyond current capabilities. We design our instruments with these goals in mind and have assembled a team to solve the many challenges to achieve this.

How advanced is the bioprinting community in Europe?

The 3D bioprinting field is several years behind mainstream 3D printing, with the industrialization of the instruments, biomaterials, and cells required before bioprinting can progress to commercial-scale biofabrication. However, as with continued development seen in 3D printing, the technology convergence required for tissue and organ printing that changes medical treatments will become a reality through the efforts of engineering companies like regenHU, biomaterial developers, and human cell expansion technologies, being combined in projects such as OrganTrans.

As the newly appointed CEO of the company, how do you feel taking on this project?

Successfully entering the OrganTrans consortium is just one part of the company. regenHU investors see my arrival as the catalyst to bring regenHU to the next stage in its evolution. Our goal remains the production of industrial biofabrication instruments capable of delivering the medical potential of bioprinting, novel bioinks, and stem cells. To achieve this, we are enhancing the team and structure of the company, bringing forward the development of new technologies and increasing our global footprint to better support our collaborative partners. I have spent many years in regenerative medicine and pharma and can see the potential of bioprinting to revolutionize many areas of medical science, so joining regenHU was an easy choice. As CEO, my main role is to provide the right support structure to enable our entrepreneurial engineering teams to thrive and be brave enough to push boundaries. Additionally, as we cannot achieve our end goal on our own, I am here to nurture the important connections with our user community. Only by listening to their valuable insights and solving problems with them, we will push the technology onward.

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Texas A&M Researchers Make “NICE” Bioinks to Create Functional Bone Tissues

Managing bone defects and injuries using traditional treatments can be slow and expensive. When bones break, bone cells can usually repair them, unless the break is too large. In that case, clinicians have historically turned to bone grafts using non-essential segments of bone taken from other parts of the same patient; bone from the hips, pelvis, chin, or ribs can do the job. Unfortunately, this requires additional surgeries, which translates into more pain for patients, and basically, there is a limit to how much non-essential bone surgeons can take from a patient.

As in many fields, bioprinting is disrupting the way healthcare specialists think about solving problems. So with an estimated 500,000 annual bone grafting procedures in the United States and more than 2 million around the world, an efficient bone substitute could change millions of lives. In a search to fabricate patient-specific, implantable 3D constructs for regenerative medicine, scientists in the Department of Biomedical Engineering at Texas A&M University have developed a new bioink formulation for 3D bone bioprinting called NICE, which is short for Nanoengineered Ionic–Covalent Entanglement, and have gone on to demonstrate that this bioink can precisely reconstruct large bone structures based upon CT scans that were obtained from actual patients.

Led by Akhilesh K. Gaharwar, an associate professor in the Department of Biomedical Engineering, the research group developed a highly printable bioink as a platform to generate anatomical-scale functional tissues. Their study was recently published in the American Chemical Society’s Applied Materials and Interfaces scientific journal, whereby they state that the NICE bioinks allow precise control over printability, mechanical properties, and degradation characteristics, enabling custom 3D fabrication of mechanically resilient, cellularized structures.

Bioprinting requires cell-laden biomaterials that can flow through a nozzle like a liquid, but solidify almost as soon as they’re deposited. This is why bioinks need to act as both cell carriers and structural components, requiring them to be highly printable while providing a robust and cell‐friendly microenvironment. However, the research group realized that many current bioinks lack sufficient biocompatibility, printability, structural stability, and tissue‐specific functions needed to translate this technology to preclinical and clinal applications.

To address this issue, Gaharwar and his team are leading efforts in developing the more advanced NICE bioinks, essentially a combination of two reinforcement approaches, ionic-covalent entanglement, and nanoreinforcement. In fact, the researchers claim that to design the NICE reinforced bioinks for osteogenic tissue bioprinting, the bioink must be highly printable, mechanically strong, induce osteogenic differentiation, and be biodegradable. However, the difficulty of combining these requirements into a single bioink has been a major obstacle in bioprinting since its inception. So by combining these two distinct reinforcement methods, NICE becomes a robust and superior bioink while providing a highly hydrated and cell-friendly microenvironment for bone bioprinting.

NICE printed structures are highly flexible and resilient, as seen in these 3D printed tube structures that can be completely collapsed and quickly regain their shape (Credit: Texas A&M Engineering)

According to Texas A&M Today, Gaharwar said that developing replacement bone tissues could create exciting new treatments for patients suffering from arthritis, bone fractures, dental infections, and craniofacial defects.

“The next milestone in 3D bioprinting is the maturation of bioprinted constructs toward the generation of functional tissues,” Gaharwar said. “Our study demonstrates that NICE bioink developed in our lab can be used to engineer 3D-functional bone tissues.”

NICE bioinks have three major components: covalently crosslinkable gelatin methacryloyl (GelMA), ionically crosslinkable kappa-carrageenan (kCA), and electrostatically charged nanosilicates (Laponite XLG, obtained from BYK Additives & Instruments).
To bioprint scaffolds that can demonstrate potential clinical uses, the team used their osteoinductive NICE bioinks. Then human mesenchymal stem cells (hMSCs) were encapsulated in the NICE bioink and bioprinted into 3D scaffolds. Once bioprinting was complete, this cell-laden 3D printed NICE structures were crosslinked to form stronger scaffolds. This technique has allowed the lab to produce full-scale, cell-friendly reconstructions of human body parts, including ears, blood vessels, cartilage and even bone segments.

hMSCs are encapsulated in the NICE bioink and cell-laden scaffolds are printed (Credit: Texas A&M Engineering)

Soon after bioprinting, the enclosed cells start depositing new proteins rich in a cartilage-like extracellular matrix that subsequently calcifies to form a mineralized bone over a three-month period. Texas A&M stated that almost five percent of these printed scaffolds consisted of calcium, which is similar to cancellous bone, the network of spongy tissue typically found in vertebral bones.

The scaffolds are initially transparent but turn translucent due to remodeling and deposition of nascent proteins after 60 days (Credit: Texas A&M Engineering)

To understand how these bioprinted structures induce stem cell differentiation, the team worked with Irtisha Singh from the Texas A&M Health Science Center, who served as a co-investigator, to use a next-generation genomics technique called whole transcriptome sequencing (RNA-seq) technology, which takes a snapshot of all genetic communication inside the cell at a given moment.
As for the bioprinting, the researchers modified a commercial ANET A8 3D printer kit to utilize screw extrusion. They replaced the thermoplastic extruder assembly with a 3D printed screw extruder assembly, which holds a stepper motor, guide rail, and a modified clay extruder.

To illustrate the practical utility of NICE bioinks for bone tissue reconstruction, the team demonstrated how to create full-scale bioprinted implants customized for craniofacial defects on real patient CT scans. Relying entirely on open-source software, they used the free 3D modeling software Meshmixer to process the models and create bone defects, and the 3D printing applications PrusaSlicer and Repetier Host to bioprint the scaffolds. After bioprinting, the scaffold was crosslinked and implanted in a thermoplastic model of the lower jaw to demonstrate the closeness of fit. Strength of fit was also demonstrated by injecting and crosslinking NICE bioink between two sections of a full-thickness fracture to prove that NICE is able to quickly adhere surfaces together and resist shearing and delamination forces.

Funded by the National Institutes of Health (NIH)’s Director’s New Innovator Award, a National Science Foundation (NSF)’s Award and an X-Grant from Texas A&M University, the researchers suggest they have discovered a new way to design and produce 3D bioprinted bone tissue to benefit bone regeneration.

Moreover, Gaharwar claims to have demonstrated that the highly printable NICE bioinks can precisely reconstruct large bone structures from CT scans obtained from actual patients. The aim of the research is to enable patient-specific bioprinting of bone scaffolds to precisely match their injuries. The researchers stated their desire to have this technique act as a customizable and easy to work with an alternative to autografts that will provide surgeons with greater options for bone surgery. And with the ultimate goal of getting NICE bioink technology from bench to bedside, Gaharwar’s team plans to establish the in vivo functionality of the 3D bioprinted bone tissue.

3D-bioprinted NICE scaffolds can be used for bone regeneration (Credit: Texas A&M Engineering)

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New Study Discusses Unmet Clinical Needs Being Addressed by 3D Printing

3D printing continues to make a huge impact on the medical field – the evidence more than speaks for itself. But this important work is not done yet. A team of researchers based at the University of Utah recently published a review paper that, as Yong Lin Kong, PhD, an assistant professor in the university’s Department of Mechanical Engineering, told, “highlights the progress of 3D printing technologies in addressing unmet clinical needs.”

The paper, titled “Addressing Unmet Clinical Needs with 3D Printing Technologies” and published in Advanced Healthcare Materials, was written by Udayan Ghosh, Shen Ning with the Boston University School of Medicine, Yuzhu Wang, and Professor Kong.

A) 3D printed biomimetic bone environment for evaluating breast cancer bone metastasis; B) 3D printed network guide for regenerating damaged nerve plexuses; C) 3D printed titanium prosthetic for sternocostal reconstruction; D) An endothelialized myocardium by 3D printing endothelial cells encompassed within micro-fibrous hydrogel scaffolds; E) 3D printed personalized ocular prosthesis; F) Bionic ears; G) Hollow micrometer-scale microneedles; H) 3D printed pelvic implant.

The abstract reads, “Recent advances in 3D printing have enabled the creation of novel 3D constructs and devices with an unprecedented level of complexity, properties, and functionalities. In contrast to manufacturing techniques developed for mass production, 3D printing encompasses a broad class of fabrication technologies that can enable 1) the creation of highly customized and optimized 3D physical architectures from digital designs; 2) the synergistic integration of properties and functionalities of distinct classes of materials to create novel hybrid devices; and 3) a biocompatible fabrication approach that facilitates the creation and cointegration of biological constructs and systems. This progress report describes how these capabilities can potentially address a myriad of unmet clinical needs.”

The paper first looks at providing structural support for skeletal and tubular organs with 3D printed prosthetics in order to help people regain some of the functions they’ve lost, and then moves on to novel drug delivery strategies and organ-on-a-chip systems.

“Fourth, the developments of 3D-printed tissue and organ regeneration are explored,” the researchers explain in the paper. “Finally, the potential for seamless integration of engineered organs with active devices by leveraging the versatility of multimaterial 3D printing is envisioned.”

Society has been transformed by mass production, which allows parts to be manufactured at a far lower cost than hiring manual labor. However, that makes it difficult, and more expensive, to find customized products.

The researchers say in the paper, “Instead of optimizing for individual need and comfort, mass production manufacturing has compelled society to tolerate a finite set of prescribed designs determined by the overall market.”

Mass production doesn’t really address the complexity of the human body, and the majority of typical FDA-approved medical devices are not tailor-made to a patient’s specifications, which can many different issues that affect a person’s quality of life. But now, more and more physicians are investigating the use of 3D printing as it pertains to making cost-effective, customized devices.

“Indeed, 3D printing of biocompatible materials can create patient-specific prosthetics tailored to each patient’s unique anatomy and needs,” the researchers wrote.

3D printed prosthetics can help decrease discomfort, as they’re fitted to specific people, and at the same time are less expensive while also being more accessible. One specific, and very important, unmet clinical need that 3D printing can help with is creating functioning upper limb prostheses for children, so that they can grasp things in order to perform their basic daily activities. It’s hard to provide children with well-fitting prosthetics, as they grow so rapidly; that’s why a 3D printed version is a far better option.

Mock-up prototype of a microneedle array.

3D printed devices are also being used to help develop novel drug delivery strategies, from customized mouthguards and vaccines to microneedles and micro-rockets.

The researchers wrote, “Here, 3D printing enables the creation of unique architectures to allow painless delivery of therapeutic agents and tailored drug release profiles.”

Current strategies can be difficult when attempting to enable accurate drug delivery, but 3D printing has the potential to, as the paper puts it, “overcome these long- standing challenges.”

“3D printing introduced a potential opportunity for developing personalized, controlled, and precise drug delivery systems,” the researchers explained. “This technology achieves precise control of dosage in accordance with the size and dispensary mechanism of the design. Biocompatible material also allows for long-term implantation or retention while continuously dispensing controlled volumes with the potential to evolve into a highly efficient sensor-controlled drug dispensing system.”

3D printing is also being used now to address the unmet clinical need of the organ-on-a-chip platform, as it can summarize microenvironments in order to gain a more thorough understanding of cellular mechanics.

A) 3D printed in vitro human renal proximal tubules embedded within an extracellular matrix and housed in perfusable tissue chips. B) Customizable 3D printed nervous system-on-a-chip. The circular pattern of 3D printed silicone tri-microchannels designed for axonal guidance (L). A microscopy image shows three parallel microchannels of neurons and axons (green) in a chamber (R).

“Tissue/lab-on-a-chip, synonymous to biomedical application of microfluidics, is an advantageous and cost-effective way to investigate basic research questions. Analyzing fluids at the micrometer scale using microfluidic device holds immense promises for biological research,” the researchers said in the paper.

Ongoing research into tissues-on-a-chip is working to develop tissue chips that can act as accurate models for a specific organ’s function and structure, and 3D printing is the perfect technology for the job. Research also continues for the use of 3D bioprinting in tissue regeneration, as it can be used to create biocompatible constructs and 3D printed scaffolds to help regrow damaged tissues and organs, such as ears.

The researchers explained, “Bone tissue–engineered 3D constructs are more advantageous than 2D cell cultures due to the structure and mechanical composition 3D printing can produce to mimic the bone tissue microenvironment.”

Liver on a chip

Finally, the team touched on multimaterial 3D printing, which can help speed up “the creation of bioelectronic constructs to impart active functionalities to an otherwise passive construct.”

“The incorporation of electronics into biomedical devices and biological scaffolds is a foundational concept, which when applied, can mimic and even augment the complex functionalities of biological systems,” the researchers continued.

By integrating medical instruments with electronics, we can develop sophisticated new bioelectronic devices that are actually able to process feedback from the human body. The level of integration demonstrated by conventional fabrication techniques is rather limited, but using 3D printing to achieve these devices opens up far more possibilities – even, as the researchers explain, “the ability to mimic or surpass complex functionalities intrinsic to biological organs.”

“To date, demonstrations of a seamless bioelectronics 3D printing have been limited to passive electronic components, such as conductive traces and capacitors,” the researchers explained. “The integration of active electronic devices could impart an otherwise passive construct with optical, sensing, and computational capabilities.

“We anticipate that similar approaches can develop 3D printing strategies of various classes of active electronics. Nevertheless, the biocompatibility of such approach must be critically assessed to ascertain a full translational result from the bench to the bedside.

There’s a lot to think about here, but one thing is certain – the research into how we can address a myriad of unmet clinical needs with 3D printing should continue.

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