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An Integrated Approach to Three-Dimensional Bioprinting at Subfreezing Temperatures

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An Integrated Approach to Three-Dimensional Bioprinting at Subfreezing Temperatures An Integrated Approach to Three-Dimensional Bioprinting at Subfreezing Temperatures By Gideon C Ukpai A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Engineering - Mechanical Engineering in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Boris Rubinsky, Chair Professor Chris Dames Professor Kevin Healy Summer 2020 An Integrated Approach to Three-Dimensional Bioprinting at Subfreezing Temperatures Copyright 2020 By Gideon Ukpai 1 Abstract An Integrated Approach to Three-Dimensional Bioprinting at Subfreezing Temperatures by Gideon Ukpai Doctor of Philosophy in Mechanical Engineering University of California, Berkeley Professor Boris Rubinsky, Chair There are over 100,000 patients on the US transplant list alone, and millions more needing transplants globally. Many of these transplant patients have little hope of getting a replacement organ in time to ensure survival. On-demand fabrication of organs and tissues using tissue engineering could provide a solution and save the lives of millions of transplant patients and patients with end-stage organ failure. A major component of fabricating these artificial tissues and organs is the construction of a scaffold, often with the cells incorporated, that simulates the appropriate tissue environment and guides the formation of complex tissue structures. Three- dimensional (3D) bioprinting has emerged as the most promising approach for developing these scaffold constructs, but despite significant advances, the technique faces various challenges. Some factors that have thus far limited the production of clinically relevant constructs include, insufficient mechanical properties for fabrication of full-scale organs, unsustainably long print times, and poor survival of the biological matter during and after printing due to lack of vascularization. Current techniques and emerging methods still fall short of addressing some of these limitations, so in order for continued advancement in this field, alternative approaches are needed. This work explores in detail a novel technique of doing 3D bioprinting at subfreezing temperatures, called 3D cryoprinting. 3D cryoprinting incorporates the benefits of ice formation at subfreezing temperatures and the flexibility afforded by super soft biomaterials to improve the fabrication of soft tissue scaffolds. This method utilizes controlled freezing to improve mechanical properties of the printed matrix while simultaneously cryopreserving the biological matter. In order to establish 3D cryoprinting as a viable alternative for 3D bioprinting, the challenges and unknown parameters associated with 3D cryoprinting such as the solidification in large objects, cell viability, structural stability during melting, and mass manufacturability are tackled. Several methods and models to control and understand freezing during cryoprinting are developed, including a thermal phase change model for controlling the freezing rate of biological matter during cryoprinting, which substantially improves the process outcome. A method that enables the preservation of the geometric shape after thawing, a crucial element to the viability of 3D cryoprinting, is also developed. And to speed up manufacture and enable mass manufacturing a modified process of cryoprinting is developed, called parallel multilayer cryolithography. The culmination of this work 2 demonstrates that 3D cryoprinting could be a viable alternative for the fabrication of complex 3D tissue and organ scaffolds, especially in cases of super soft tissue scaffolds where other bioprinting methods have proven inadequate. _____________________________ Professor Boris Rubinsky Dissertation Committee Chair i To my family ii Table of Contents Table of Contents ....................................................................................................................... ii 1. Introduction ........................................................................................................................ 1 1.1. Motivation and background ................................................................................................... 1 1.2. Current approaches to three-dimensional (3D) bioprinting ................................................... 1 1.3. Materials used for 3D bioprinting .......................................................................................... 5 1.4. Challenges in 3D bioprinting and tissue engineering .............................................................. 8 1.5. Three-dimensional (3D) bioprinting at subfreezing temperatures ......................................... 9 1.6. Thesis overview .................................................................................................................... 10 2. Control and optimization of 3D cryoprinting .................................................................... 13 2.1. Introduction ......................................................................................................................... 13 2.2. Mathematical model for 3D cryoprinting ............................................................................. 14 2.2.1. Thermal model of the phase-change problem.................................................................................15 2.2.2. Extrusion model for the printing process ........................................................................................20 2.2.3. Algorithm for 3D cryoprinting simulation ........................................................................................21 2.2.4. Thermophysical parameters for simulation .....................................................................................22 2.3. Results .................................................................................................................................. 23 2.3.1. Variation with printing speed .........................................................................................................23 2.3.2. Variation with surface temperature ................................................................................................24 2.3.3. Experimental Validation of Mathematical Model ............................................................................25 2.3.4. Addition of cryogenic cooling fluid for control ................................................................................29 2.3.5. Prediction of cell survivability .........................................................................................................32 2.4. Discussion and conclusion .................................................................................................... 33 3. Freezing modulated cross-linking for stability of fabricated frozen scaffolds ................... 36 3.1. Introduction ......................................................................................................................... 36 3.2. 1-D mathematical analysis of freezing modulated cross-linking ........................................... 38 3.2.1. Case 1: Melting of the slab is much faster than diffusion of salt ......................................................42 3.2.2. Case 2: Melting rate is comparable to the rate of the diffusion of the salt .......................................44 3.3. Results and discussion .......................................................................................................... 45 3.4. Conclusion ............................................................................................................................ 52 4. Microstructure and mechanical properties of cryoprinted constructs .............................. 54 4.1. Introduction ......................................................................................................................... 54 4.2. Analysis of directional solidification of aqueous solutions ................................................... 55 4.2.1. Mathematical model of directional device ......................................................................................55 4.2.2. Results and validation of device design ...........................................................................................62 iii 4.3. Design of directional solidification device ............................................................................ 69 4.4. Experimental studies of ice formation and microstructure using directional solidification .. 70 4.4.1. Effect of cross-linking on ice morphology........................................................................................70 4.4.2. Effect of cross-linking application sequence on resulting alginate microstructure ............................73 4.4.3. Effect of cross-linking density on alginate microstructure ...............................................................75 Effect of directional microstructure on mechanical properties of alginate.....................................................77 4.5. Discussion and conclusion .................................................................................................... 79 5. Parallel multilayer cryolithography for mass manufacturing ........................................... 82 5.1. Introduction ......................................................................................................................... 82 5.2. Principles of parallel additive manufacturing ....................................................................... 83 5.3. Device description
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