Innovative Silk Bioink for 3D Bioprinted Bone Marrow Tissue Models

The human body possesses a remarkable ability to respond to injuries by producing platelets that facilitate blood clotting. This intricate process is led by giant cells called megakaryocytes that reside in the bone marrow, inside our bones. However, the natural production of platelets does not meet the demand for transfusions required to treat millions of people suffering from blood diseases, viral infections, or chemotherapy.

Today, the primary source of platelets is from healthy donors. However, the rising need for platelet units, coupled with their remarkably brief shelf life of approximately five days, frequently leads to shortages in platelet supply. Complications arise, particularly during periods of low donation rates, such as summer, or in times of public health emergencies like pandemics. Pharmacologic therapeutic options may be valuable alternatives, though the choice of the best treatment regime is challenging. 

 

Combining silk with bioprinting to recreate human bone marrow environments

Prof. Alessandra Balduini and her team at the University of Pavia are taking this challenge head-on by initiating the EIC Transition SILKink project, which aims to produce a groundbreaking platform that combines the use of natural silk and 3D bioprinting to recreate the environment of the human bone marrow where platelets are produced. Researchers think that they can program lab-grown megakaryocytes to believe they are inside the human body and provide a sensitive system for ex vivo screening of new therapeutics directly on patients’ megakaryocytes, thus leading to the choice of the best therapeutic course and ultimately to improvements in clinical care.

The project is led by the University of Pavia in Italy, in collaboration with CELLINK Bioprinting. Partner Catalyze-Group will lend their commercial expertise to develop an optimal market access strategy for SILKink.

Prof. Alessandra Balduini, University of Pavia

Crafting a functionalized bioink that could mimic the softness of bone marrow

For over 15 years, Alessandra has been dedicated to understanding the mechanisms of platelet production in the human bone marrow, as well as the clinical aspects of human diseases associated with platelet and clotting processes. Her team developed an early 3D model of silk-bone marrow which served as a foundation and starting point for the project. Although the existing model was functional, it lacked the appropriate stiffness. The team goal was to standardize the model to allow usage for drug testing applications and personalized medicine.  

Alessandra’s team turned to bioprinting to solve these challenges. Before any printing occurred, the team first needed to identify and develop a bioink that could be used to produce the bone marrow model. It was imperative that the bioink was soft enough to mimic the softness of bone marrow. 

“We wanted to create a system that we could control and manipulate in terms of functionalization, but, at the same time, it was vital that we could replicate the softness of the native bone marrow tissue.”

– Prof. Alessandra Balduini, University of Pavia

Not all biomaterials are suitable for platelets, as some hinder megakaryocytes from generating platelets or lead to premature exhaustion of newly formed platelets. Furthermore, the 3D structure needs to consist of extracellular components to support the differentiation of megakaryocytes, without adversely activating the platelets. 

Leveraging what came before

Drawing on their previous experience with silk and leveraging CELLINK’s expertise in bioprinting, the group in Pavia, developed a new silk-based bioink formulation. The silk used is a natural biomaterial produced by Bombyx mori silkworm cocoons. This protein is particularly suitable for platelets due to its self-assembly ability, robust mechanical properties, biocompatibility and biodegradability. 

Using the BIO X, the team successfully 3D bioprinted patient hematopoietic stem and progenitor cells into a liquid silk-based bioink which then solidified, maintaining the structure, and supporting the physiological process of platelet production. In comparison to other research endeavors, this model demonstrated superior platelet production, attributed to its accurate mimicry of bone marrow characteristics. 

“The fusion of advanced bioprinting technology and silk fibroin biomaterial has empowered us to create a cutting-edge bone marrow model allowing in vitro megakaryopoiesis and platelet production, marking a breakthrough in personalized medicine for diseases that cause low blood platelet count, like thrombocytopenia.”

– Pierre-Alexandre Laurent, PhD, CELLINK

Team photo at CELLINK HQ, Gothenburg.

By developing a new bioink and incorporating bioprinting into their project, the team was able to standardize and streamline the production of the functional 3D bone marrow model. This means that the model can be used as a novel screening technology in the pharmaceutical industry to predict the therapeutic effect of compounds on platelet number or function. Evaluating effective drugs is a costly process as animal models usually prove to be unreliable predictors of human outcomes. The bioprinted model offers a refined ex vivo screening system for assessing the efficacy of new therapeutic drugs. 

“Through bioprinting, we gained the capability to consistently regulate crucial printing parameters such as temperature, cell count, and structure. This enabled us to exert precise control over platelet production, resulting in the development of a system that allows for effective testing of drug efficacy.”

– Prof. Alessandra Balduini, University of Pavia

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