More than 100,000 people are awaiting an organ transplant in the United States, with a new candidate added to the list every 10 minutes. Even if the transplant is carried out successfully, recipients must take immunosuppressive medications, elevating their risk of broader infections, and adhere to a strict lifestyle for the rest of their lives鈥攁ll while facing the possibility that their body could reject the donated organ at any time.
Scientists have been from a patient鈥檚 own cells for decades in an attempt to solve this problem. But a major obstacle to realizing lab-grown organs is replicating the scale and complexity of the body鈥檚 vascular networks, especially capillaries. These microvessels crisscross each organ to deliver oxygen and other nutrients to every living cell, making them an essential component of any useful bioengineered tissue model.
To overcome this central challenge, , the Advanced Materials and Manufacturing Collegiate Professor in the at the University of Notre Dame, and colleagues have created a novel hybrid bioprinting technique that produces vascular networks containing capillaries fewer than 10 micrometers in diameter鈥攕maller than that of the finest human hair. The work is detailed that was featured on a recent cover of .
鈥淧rinting blood vessels that mimic natural living systems is very difficult since the vessels vary in size,鈥� Zhang said. 鈥淕etting the smallest vessels right, without losing scalability and structural integrity, has remained one of the greatest challenges to current state-of-the-art bioprinting.鈥�
Zhang鈥檚 new approach integrates two distinctive 3D printing techniques and incorporates machine learning to autonomously optimize printing parameters for each desired vascular configuration. The hybrid method, developed in collaboration with Y. Shrike Zhang, associate professor of medicine at Harvard Medical 91视频 and Brigham and Women鈥檚 Hospital, produced stable one-, two- and three-dimensional vascular structures, which were then successfully lined with living cells.
鈥淲e鈥檝e reached a major breakthrough in the field of bioprinting,鈥� said Zhang, an affiliate of Notre Dame鈥檚 and . 鈥淎chieving capillary-scale resolution in bioprinting is an important step towards engineering fully functional tissues and complete organs.鈥�
Attaining such fine resolution required the harmonious integration of two complementary printing technologies. The matrix鈥攁 soft, gel-like scaffold that mimics real tissue鈥攊s printed by extrusion, a widely used method that uses pressure to dispense biomaterials one layer at a time. Once a section of the matrix is printed, thin threads of gelatin are deposited within by aerosol jet printing (AJP), which will eventually be removed to leave behind channels embedded inside the matrix.
Aerodynamic focusing using a sheath flow, a unique feature of AJP, enables dynamic adjustments and the printing of the channel sizes from hundreds of micrometers down to several micrometers, which mimic the varied architecture of natural vessels. Since small changes to the ink flow rate and sheath gas flow rate affect the ultimate size of the printed channel, the researchers developed and integrated a machine learning framework to efficiently determine the ideal combination of printing parameters for a given channel size.
鈥淢achine learning is a very powerful tool that helps us to identify the optimal parameters much more quickly compared with the conventional trial-and-error method,鈥� Zhang said. 鈥淚ncorporating autonomous optimization has yielded a large boost in efficiency for realizing the desired quality and precision of the printed channels.鈥�
Applied together, the hybrid printing approach successfully fabricated hierarchical vascular networks in one, two and three dimensions. Select channels were then seeded with endothelial cells, which line the body鈥檚 blood and lymphatic vessels, and yielded the formation of single-cell layers akin to those seen within living human tissues.
鈥淲e are very pleased to see living cells rapidly attach and spread along the inner walls of the channels, ultimately replicating the barrier function of real human capillaries,鈥� Zhang said. 鈥淚t鈥檚 a big step forward in showing that our hybrid-printed networks are capable of supporting living tissue structures without leakage."
Biomimetic tissue models such as Zhang鈥檚 offer a promising route for therapeutic discovery, in addition to regenerative medicine and organ engineering. By accurately mimicking human vascular networks down to the smallest capillaries, such platforms can serve as new 鈥渙rgan-on-a-chip鈥� models to test drugs for safety and efficacy. Further, the use of patient-specific cells to form these models offers a potential path for personalized medicine, where therapeutic responses could be evaluated within the model system prior to full-scale treatment.
Zhang鈥檚 ultimate aim is to develop an autonomous, intelligent bioprinter to produce fully functional tissues and organs such as the heart, kidney and liver. In the near term, his research group and their collaborators at Harvard to design and build an even more powerful version of Zhang鈥檚 hybrid bioprinter and pursue the fabrication of lab-grown organs.
鈥淭here are so many people waiting for an organ transplant, and the ability to print organs in the lab has the potential to transform lives by helping humans to live longer and live healthier,鈥� Zhang said. 鈥淲e are not simply developing better technology, but shining light on a new future for organ transplantation and human health.鈥�
This study was supported by the National Institutes of Health. The instrumentation and staff of several Notre Dame core facilities supported this work: the core facility, the , the and the .
Contact: Brandi Wampler, associate director of media relations, 574-631-2632, brandiwampler@nd.edu