People Innovation Excellence

How to print a better human

ISE Magazine August 2018 Volume Number: 50

By Shantanab Dinda, Yang Wu and Ibrahim Tarik Ozbolat

Time to develop bioprinting processes

3-D bioprinting technology has shown immense potential in the last few years, especially with the developments in fabrication of scaffolds and the possibility of printing in-situ and complete organs.

To this effect, additive manufacturing is gradually proving to be a cornerstone in bioprinting research, with the underlying principles of both technologies being the same – compiling raw materials together in a controlled, layer-wise manner to form 3-D objects, in contrast to traditional machining, which removes material in a subtractive manner.

In biological applications, additive manufacturing forms complex 3-D biocompatible structures using automated deposition of biocompatible materials and cells on an appropriate surface or substrate based on a computer-aided design (CAD) drawing. Using this, one can control the mechanical and physical parameters of a printed scaffold, such as the shape, size and internals porosity.

Though metal and polymer 3-D printers have been developed over the years for higher precision and accuracy in part fabrication, bioprinters are still at a nascent stage, with printing organs and functional tissues with entire structures still needing intervention from external sources, especially the use of additional materials to make sure cells adhere to the substrate. The constituent cells require bioinks: Secondary materials for propagating adhesion and generating a shape for the scaffold. Bioinks may be complex to prepare and use, as they must deliver good biocompatibility and mechanical strength that can be used to achieve biological function.

One of the most problematic factors today is the limitation in vascularization of bioprinted tissues, which are necessary to effectively transport nutrients and waste for the constituent cells. Consequently, this limits the thickness of the tissue that can be fabricated due to cell death at the tissue center, with very few exceptions such as planar or tubular tissues like skin and blood vessels. Additionally, existing artificially developed organs do not provide the same degree of functionality as their natural counterparts.

Tissue engineering has come a long way over the last two decades. As it moves forward, tissue-engineered organs are becoming more accurate and promising. Decreases in re-establishment time, supply chain logistics and cost should also be addressed before such organs can be used in clinical medicine.

Tissue engineering and bioprinting at Penn State

At first glance, an industrial and systems engineer may seem out of place in such a setting, but such research topics necessitate collaborative work – both internal and external, and an industrial and systems engineer’s skills are invaluable for the supply chain, manufacturing and management-related activities that are involved in this lab.

Considerable focus is given to studies on connective tissues, with several ongoing projects researching bone and cartilage. A major study underway aims to develop a novel, printable bioink that can facilitate bone regeneration for intra-operative bioprinting of bone tissue constructs for craniomaxillofacial repair applications.

In order to accomplish these goals, researchers have developed a new printable bioink that does not require any pre- or post-processing, including chemical, physical or photocrosslinking, which made it suitable for bioprinting directly in the body (intraoperative). This research will be the first attempt toward intraoperative bioprinting of advanced bone tissue constructs with controlled morphology, spatial bioink deposition and geometry that will mimic the native bone tissue properties and accelerate bone tissue regeneration..

The use of biodegradable metal implants is rare in literature, making this a highly lucrative study for repairing load-bearing bones such as those in our legs. Such studies are targeted to culminate with animal trials, which showcase the practicality of the results and provide the much-needed push for human trials.

In human joints, firm and rubbery cartilage material covers the end of each bone, which provides a smooth and gliding surface for joint motion and acts as a cushion between the bones. With time, this cartilage breaks down, leading to pain and other problems of the joint. Current clinical treatments are often complicated, costly, yielding mechanically inferior structures with unsatisfactory results in the long term. Often, patients eventually need joint replacement to restore normal function.

The research team at Penn State is working on an alternate solution, obtaining human fat cells from patients who undergo fat removal surgery and differentiate them to chondrocytes, the cartilage cells. These cells are then injected into customized hydrogel capsules to generate cell aggregates in the form of strands. The strands are able to express cartilage-specific genes and proteins, which provide the mechanical strength of the cartilage. The strands are then used as a bioink to 3-D print biomimetic human articular cartilage. Bioprinting scalable tissue strands will enable the team to rapidly fabricate cartilage at clinically relevant volumes, demonstrating its clinical potential for treating chondral injury and osteoarthritis using cells from the same patient.

Skin is the largest organ in the human body. It protects our internal organs, regulates our body temperature and helps us to physically understand everything around us. Though skin is a simple organ, it is complex at the single cell level with an anisotropic distribution of various cell types and the extracellular matrix proteins.

Engineering functional skin tissue with native characteristics is challenging at present. The research group at Penn State aims to regenerate functional skin tissue by bioprinting bioinks containing living cells directly into the skin lesion sites. The team uses droplet-based bioprinting to precisely place the bioink droplets to make the engineering of functional skin tissue possible.

Organ on a chip is a 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems. Organ on a chip is an upcoming and lucrative topic in medicine that, if properly developed, has the potential to eliminate animal testing. The research group is currently working on a 3-D vascularized tissue on a chip, aiming to invent a method for printing hydrogels and other alternatives to existing hydrogels.

This project optimizes the design of the device, starting with the perfusion chip, followed by manufacturing external housing of the device to provide structural stability. Various material and 3-D printing techniques are being investigated to find the best match for device parts.

The project also takes a step toward 3-D complex channel printing using fugitive ink. Computer-aided flow simulation of complex channels is being used to find out the optimal flow of perfusion.

To test the functionality of the device, cell viability is also being analyzed. When completed, drug testing can be conducted using this proposed device.

Building on this, the lab has moved to apply organ on a chip in cancer research, developing tumor-on-a-chip based models for studying cancer metastasis and gaining meaningful insights into cancer progression. This research is being done in collaboration with Dr. Derya Unutmaz, a medical doctor from Jackson Labs, who provides engineered cells that are implemented to kill cancer cells. This occurs in a complex environment which, if properly estimated and mimicked in the lab, can help us understand how the various types of cells in the tumor microenvironment aid the spread of cancer.

Eventually, these tumor models will be bioprinted to produce high throughput and reproducible platforms to study disease progression, mimic tumor hierarchy and investigate the role of immune cells in cancer.

This wide array of research projects showcases the reliance of tissue engineering research on automation and process control. With the diversity in research topics and applications comes the need for diversity in the researchers conducting these studies. An industrial and systems engineer’s experience with manufacturing systems and logistics and the technical know-how about the needs and expectations of the industry allows such a lab to bridge the ever-widening gap between research and industry.

Where does the future of bioprinting lie?

Bioprinting is moving toward becoming the primary method of fabricating tissues and organs for medical use, with a long-term goal of replacing animal testing, grafts and transplants. With precise control, the possibility of forming complex tissue types and giant strides in bioink development, bioprinting epitomizes the integration of sciences and engineering.

There is still some fine-tuning required in several areas, primarily the engineering challenges provided by vascularization and shape retention for complex constructs. Bioprinters cannot yet pattern material and cells at the scale and complexity desired by the human body. As the field develops and research migrates toward application in clinical trials, the regulations and industrial requirements associated with it will become more restrictive.

The need for optimization in printer, tissue and toolpath design will subsequently become more important, and industrial and systems engineers will find themselves striving to meet

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