The growing imbalance between the supply and demand of organs for transplantation has been a critical problem within the field, leading to perpetually long waiting periods or even death for patients before receiving a necessary transplant. Engineering tissue or even whole organs has been a moonshot idea that has led to some promising results that attempt to alleviate this massive problem. First described as an “interdisciplinary field that applies the principles of engineering and the life sciences,”1 tissue engineering combines material engineering with biological systems given specific stimulation to generate functional tissues. Engineered tissues or even whole organs have been accomplished within a laboratory setting on varying size scales and organ types stemming simple tissues such as cartilage2 to large human-sized organs.3
Techniques to engineer tissues have progressed drastically in the over 25 years that the field has formally existed. Progression of techniques has opened the potential to provide personalized tissues and organs on demand when needed for transplantation. One of the most promising and newest techniques currently being investigated is 3-dimensional bioprinting. Bioprinting was first established in 20034 as a marriage of additive manufacturing technologies with polymers used in scaffolding for tissue engineering. Tissues are engineered in a layer by layer approach built off of a computer-aided design (CAD). CADs can be generated from an imaging modality of a patient such as a computed tomography or MRI scan to generate tissues that completely match the patient’s own. Different polymers, cells, or some combination thereof can be printed and built to engineer large tissues or whole organs.
Initially, soft protein hydrogels could not be used with the bioprinting platform, although these types of proteins have been predominately used in tissue engineering due to their prevalence within the native extracellular matrix. Thus far, these soft proteins could only be used in 2-dimensional or very simple and small 3-dimensional layers until the establishment of FRESH bioprinting by Hinton et al5 in 2015. FRESH bioprinting stands for “freeform reversible embedding of suspended hydrogels” and uses a thermoreversible support bath to suspend the printed structures from soft protein hydrogels including collagen or alginate bioprinted into complex structures. The support bath used, a manipulated gelatin slurry, allows for the hydrogels to be suspended to fully polymerize and form tissues. The bath can then be thermally melted away at normal cell culture incubator temperatures, leaving behind the bioprinted hydrogel tissue or organ. FRESH bioprinting opened up endless amount of opportunities within the field, representing a turning point for the prospects of whole organs printing on demand. This approach has recently been updated and improved upon by the same group in a recent publication by Lee et al.6 In this update, termed FRESH 2.0, high resolution of structures could be printed through controlling the support bath’s material properties and pH of the printed collagen. The authors demonstrated the capabilities of FRESH 2.0 by printing a cardiac ventricle model that showed visible contractions by day 4, maintained until the end of the observation period at 28 days. These models had native-esque calcium handling properties as demonstrated through point-stimulations. Lee et al6 further demonstrated FRESH 2.0’s ability to engineer patent small diameter vessels in a few different collagen printed models. Most impressively, the vascular tree of a human heart was built from a CAD model taken from an MRI. The vasculature tree was bioprinted out of collagen and able to handle perfusion of dyes down to a 100 μm size. This CAD model was expanded upon and the authors showed the capabilities to print a functional trileaflet heart valve and a whole neonatal size scaled collagen print of a heart, including all 4 chambers, trabeculation, and aortic branches.
Similarly, a different group, Noor et al7 also showed the capability to bioprint a whole anatomical model of the heart out of natural soft biopolymers. In this publication, the authors pushed the field closer to a completely personalized tissue source by using decellularized omentum to act as the polymer within their bioprinted heart. Decellularized omentum can be patient-derived and would have some added small molecular benefits when compared with singularly printed collagen. The work by Noor et al7 also included induced pluripotent stem cell-derived cardiomyocytes within their bioprinted heart. Induced pluripotent stem cell-derived cardiomyocytes, like the omentum, can be patient sourced, demonstrating the potential to provide a completely personalized human organ on demand.
There are still improvements that need to be made before the full potential of bioprinting could be realized and translated into the clinic. Improvements include printing small enough diameter vessels that are patent to provide the necessary blood flow throughout the entirety of the printed organs. Recently it has been shown that vessels can be printed within the engineered tissues. This technique called sacrificial writing into functional tissue bioprinting8 allows for patent vessels to be directly printed within the tissue. Additional improvements moving forward will need to include an improved control of printing over-time and increasing the complexities and specializations of the tissues being printed.
FRESH bioprinting has expanded the technique in a way that may eventually allow for bioprinted organs to be available and in use within the clinic. This technique is the next evolutionary step in the lifeline of tissue engineering, and it is the most promising one to date. As these techniques improve and the field of tissue engineering is further expanded upon, one day we may be able to lower or even eliminate the organ transplant waitlist by providing personalized organs on demand.
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3. Guyette JP, Charest JM, Mills RW, et al. Bioengineering human myocardium on native extracellular matrix. Circ Res. 2016; 118:56–72
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5. Hinton TJ, Jallerat Q, Palchesko RN, et al. Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels. Sci Adv. 2015; 1:e1500758
6. Lee A, Hudson AR, Shiwarski DJ, et al. 3D bioprinting of collagen to rebuild components of the human heart. Science. 2019; 365:482–487
7. Noor N, Shapira A, Edri R, et al. 3D printing of personalized thick and perfusable cardiac patches and hearts. Adv Sci (Weinh). 2019; 6:1900344
8. Skylar-Scott MA, Uzel SGM, Nam LL, et al. Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels. Sci Adv. 2019; 5:eaaw2459