Chasing The Holy Grail of Regenerative Medicine

Solid organ fabrication is an ultimate goal of Regenerative Medicine. Since the introduction of Tissue Engineering in 1993, significant advancements have been made to regenerate in vitro culture or tissue platforms.

Relatively simple flat or tubular organs are already in (pre)clinical trials and a few commercial products are in market, but the road to more complex, high demand, solid organs including heart, kidney and lung will require substantive technical advancement. There are two emerging technologies for solid organ fabrication. One is decellularization of cadaveric organs followed by repopulation with terminally differentiated or progenitor cells. The other is 3D bioprinting to deposit cell-laden bio-inks to attain complex tissue architecture.

Decellularization began with great promise to regenerate cadaveric organs while overcoming transplant rejection and possibly alleviating perpetual shortage of donated organs. The most recent human decellularized heart was repopulated with RNA-induced PSCs to differentiate cardiomyocytes to avoid the risk of genetic modification of iPSCs. Although the recellularized cardiac slices and fibers maintained beating phenotypes, sarcomeric structures, and electromechanical function, the whole heart scaffold could not exhibit the same extent of functionality that was attained in the cardiac slice and fibers. Thus progress at the organ level scale with decellularized tissue is still in its infancy, but is advancing.

3D bioprinting of tissues, especially of soft tissues is also in its infancy. 3D bioprinting can guide the placement of cell and supporting matrix at levels corresponding to the native tissue. Many 3D bioprinting technologies already showed printed cells maintain good viability. The next step is to create a solid organ with PSCs at an appropriate differentiation stage for transplantation. Further, PSCs or progenitors in bio-inks need to be protected from uncontrolled differentiation during printing and their differentiation, proliferation, and migration should be precisely guided by spatially defined cues from matrices. In vivo or in vitro maturation should be accompanied either by biochemical signaling or electromechanical stimulation to create a functional organ. Despite these challenges, 3D bioprinting technologies are just beginning to achieve smaller goals for regenerative medicine application including in vitro model systems and drug testing.

4D printing technology has emerged as well – conferring printed 3D structures with the ability to change their form or function with time under stimuli such as pressure, temperature, wind, water or light. A candidate material for 4D printing is stimuli-responsive hydrogels mimicking the dynamics of the ECM, where the hydrogel material forms a pre-defined 3D configuration. Inspired by nastic plant motion, a calla lily flower was printed and transformed upon swelling. This biomimetic 4D printing technology controls the orientation of cellulose fibrils embedded in a soft acrylamide hydrogel to define elastic and swelling anisotropies. During printing, the composite fibrils undergo shear-induced alignment, leading to printed filaments with anisotropic stiffness and swelling behavior along the filament length. In addition, the anisotropic swelling enables precise control over curvature, which was quantified by a mathematical model for the mechanics of anisotropic objects to manipulate the embedding of a complex surface.

In the future, decellularized tissues will continue to find their way to clinical practice as they have already for skin and blood vessel. Generation of certain tissues not amenable to decellularization and more importantly, recellularization, may benefit from current or emerging variations of 3D bio printing.

For more information on solid organ fabrication, join me at Cell & Gene Therapy Bioprocessing & Commercialization this October in Boston. And for special savings, be sure to use the VIP code “B16188BLOG” – See you this October.




About the author: Justin Gaines is a Boston-based drug discovery professional and biotech enthusiast. During his tenures he has remained active within the biomedical engineering and regenerative medicine sectors, and has remained an avid proponent of bringing together the Boston life science community. He is currently leading the Bio Pharma Networking Group across the North East – a professional life science and healthcare community spanning 6K members. View his last contribution to KNect365 Bioprocessing here



Research Reference:

Song JJ, Ott HC. Organ engineering based on decellularized matrix scaffolds. Trends Mol Med. 2011;17:424–32. doi: 10.1016/j.molmed.2011.03.005.

Eng G, Lee BW, Protas L, Gagliardi M, Brown K, Kass RS, Keller G, Robinson RB, Vunjak-Novakovic G. Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes. Nat Commun. 2016;7:10312. doi: 10.1038/ncomms10312.

Choi J, Kwon OC, Jo W, Lee HJ, Moon M-W. 4D printing technology: a review. 3D Printing and Additive Manufacturing. 2015;2:159–67.

Rosales AM, Anseth KS. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat Rev Mater. 2016;1:15012. doi: 10.1038/natrevmats.2015.12.

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