3D Printing in Parkinson's Disease Micro-model

Parkinson's disease (PD) is a neurodegenerative disease in which dopamine neurons degenerate in the brain and cause motor and non-motor symptoms such as tremors, stiffness, bradykinesia and cognitive loss. Even after breakthroughs in the pathophysiology of Parkinson's, the disease remains so enigmatic that drugs and therapies remain unexplored as well as lacking therapeutics that can prevent or reverse its onset. 3D printing has been increasingly applied in medical research in recent years, especially to create complex, highly precise models of disease mechanisms. Applying 3D printing to Parkinson's, for example, provides a novel way to construct micro-models of the complex biological landscape of the brain. They could be used for drug screening, disease modelling and the testing of therapeutic possibilities, all of which is important to Parkinson's disease research and treatment.

Figure 1. Schematic presentation of the 3D-printing process and regeneration of substantia nigra in Parkinson's disease. (Ezgi Saylam, et al.; 2021)

The Potential of 3D Printing for Disease Simulation?

This process called 3D printing or additive manufacturing involves producing three-dimensional models layer by layer from a computer model. This technology could be programmed into incredibly personalised structures, and the technology could then be programmed into biological models with highly specialised functionality that could simulate specific features of human anatomy. With Parkinson's, 3D-printed micro-models of brain tissue could be created – models that mimic the disease's dopaminergic system. The promise of 3D-printed models, then, lies in making a more detailed and reliable image of the biological structures involved in Parkinson's. The conventional models – animal models or 2-D cell cultures – are not able to recreate the dense, three-dimensional structure of the brain. Instead, 3D printing offers a level of accuracy that's previously unavailable for models that are more accurate in replicating the tissue microenvironment and so provide researchers with more pertinent and predictive systems to investigate the mechanisms of disease.

Creating 3D Parkinson's Disease Micro-Models

For Parkinson's, a goal of the micro-modelling in 3D is to model the space in which dopaminergic neurons exist and over time decay. Scientists are printing cells based on the complex organization of the human brain through 3D bioprinting, particularly in areas such as the substantia nigra, where pathology is key to the disease. One solution is printing scaffolds of biocompatible compounds, like hydrogels, capable of growing and developing human neurons, including dopaminergic neurons. Such scaffolds can be filled with stem cells or reprogrammed cells from Parkinson's patients, to give a unique and disease-specific model. The 3D model, in this way, can simulate Parkinson's's specific cellular and molecular dynamics – and it can be used to monitor disease course and evaluate treatment options. For instance, researchers have managed to print micro-brain models of the substantia nigra degenerating dopaminergic neurons in real time so that they can monitor cell death and microenvironmental changes defining Parkinson's. These models are very helpful for understanding how neurons behave as disease progresses, and how treatments might counteract damage.

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3D Printing and Parkinson's Disease Research

Drug Screening and Development

The drug-screening potential of 3D-printed Parkinson's disease micro-models is probably the best-kept hope. Most standard drug tests work only in two-dimensional cultures or animal models, which are less realistic than the human brain. Researchers can use 3D models to perform more precise screening of drug candidates – not only for effectiveness but also for safety and toxicity in a system that is a close approximation to human tissue. For example, dopaminergic pathways can be screened by 3D-printing for molecules that might either help to keep dopamine-releasing neurons alive or increase dopamine release. These models are better at measuring how drugs react with the three-dimensional brain, and will pinpoint treatment possibilities to decelerate disease or relieve symptoms. Moreover, with patient stem cells used in such models, personalized drug testing is possible where multiple potential treatments are tried on different patient models. In the past few years, 3D Parkinson's disease models have been used to examine the neuroprotective effects of a number of compounds (eg, neurotrophic factors or small molecule drugs) in ways that traditional models cannot. It enables the development of more targeted drugs, less dependent on animal models, and more effective treatments that are lab-to-clinic translated.

Understanding Disease Mechanisms

The benefits for modeling Parkinson's disease in 3D are also clear. If we copy the intricate interactions among neurons, glia and other layers of the brain's extracellular matrix, we can test how individual cellular populations lead to the development of the disease. This matters most in Parkinson's, where neuronal degeneration is tied to malfunctions in cellular machinery such as protein misfolding, mitochondrial dysfunction and inflammation. For instance, with 3D-printed models scientists have been able to study the role of microglia (immune brain cells) in Parkinson's disease. They're supposed to be responsible for the inflammatory mechanisms that drive cell death. To recreate the inflammation environment 3D, researchers could look at how neuroinflammation impairs the dopaminergic neurons' survival and determine how to adjust the immune response to treatment. Moreover, 3D models can also be created to research the effects of environmental contaminants or stress on disease. They have even tested the impact of exposure to pesticides, linked to a risk of Parkinson's, in 3D-printed Parkinson's models. In modelling combining genes and exposures to the environment, researchers can study how they relate to disease onset and progression. Personalized Medicine and Patient-Specific Models A second novel use for 3D printing in Parkinson's disease is in the design of individual patient models for personalized medicine. From cells extracted from individual patients – stem cells taken from their own tissue – scientists print micro-models describing that patient's genome and disease state. This is a way to focus drug testing and treatment. Patients could, for instance, be given individual models to determine whether a drug is going to influence a patient's neurons, and doctors would know which treatments were most effective. It might translate into more individualised treatment programmes, which can increase efficacy without increasing the risks of side effects. The patient-specific models could also be used to examine the genetic aspects of disease development, revealing why some patients are better off with certain drugs than others.

Developing Advanced Therapies

In addition to drug discovery, 3D printing could be harnessed to create new treatments for Parkinson's. The 3D-printed scaffolds for neural regeneration represent one promising area. In a process that involves developing biocompatible scaffolds that stimulate the proliferation and differentiation of dopaminergic neurons, researchers could create regenerative treatments that would replace the loss of neurons in Parkinson's patients. Moreover, 3D printing might be deployed to fabricate implantable devices or delivery systems for specialised treatments. In the field of Parkinson's, for instance, scientists are trying to create 3D-printed devices that release drugs directly into the brain – specifically into areas affected by Parkinson's. This strategy would allow neuroprotective therapies to be more efficiently delivered, the systemic side effects less severe, and patients treated more effectively.

Challenges and Future Directions

For Parkinson's disease research, 3D printing promises much but it has its challenges. There is the problem of making it look easy, by modeling out in 3D the complex shapes and functions of the brain. The human brain is extraordinarily elaborate, and it is still very hard to accurately mimic the whole range of cellular dynamics and behaviours associated with Parkinson's disease. What's more, 3D-printed models are unable to scale, especially when it comes to patient-specific models for use in clinical practice. There will be bioprinting technologies that need to become more reproducible, scalable and efficient in 3D models for them to become a clinical reality. Conclusion In Parkinson's disease, 3D printing is changing the way researchers research the disease by producing accurate, personalized models for drug screening, disease modelling and new therapies. They are so precise and detailed that researchers can explore the brain's complex biological landscape in a new way they had not previously. With the technology evolving, 3D printing will become a bigger part of how we learn about Parkinson's disease and how we make it better for people who suffer from the crippling illness.

Reference

1. Ezgi Saylam, et al.; Levodopa-Loaded 3D-Printed Poly (Lactic) Acid/Chitosan Neural Tissue Scaffold as a Promising Drug Delivery System for the Treatment of Parkinson's Disease. Applied Sciences. 2021, 11(22):10727