# Transplantable Micro-Tissue Engineered Neural Networks to Restore the Nigrostriatal Pathway in Parkinson's Disease

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2020 · —

## Abstract

ABSTRACT
Parkinson's disease (PD) is a progressive neurodegenerative disease that affects 1-2% of people over 65. The
classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia
nigra pars compacta (SNpc), resulting in a loss of their long-projecting axonal inputs to the striatum. Current
treatment strategies [e.g., dopamine replacement, deep brain stimulation (DBS)] can only minimize the
symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Therefore, we propose a novel
regenerative medicine solution, whereby custom-built micro-tissue engineered neural networks (TENNs) are
transplanted to physically replace the axonal connections from the SNpc to the striatum. Specifically, micro-
TENNs will be transplanted in rodent and porcine models of PD to directly replace SNpc neurons, restore
axonal inputs to the striatum, and ameliorate motor deficits. Our overarching hypothesis is that preformed
micro-TENNs comprised of dopaminergic neurons and long-projecting axonal tracts will survive, synaptically
integrate, and thereby physically reconstruct the nigrostriatal pathway to restore motor function in models of
nigrostriatal deafferentation. To test this hypothesis, we propose three aims: (1) Determine optimal in vitro
techniques to create dopaminergic micro-TENNs, using both differentiated neurons as well as stem-cell
derived neurons; (2) Assess micro-TENN capabilities to reconstruct the nigrostriatal pathway, restore
dopaminergic inputs, and ameliorate motor symptoms rodents; (3) Apply human-scale micro-TENNs to
reconstruct the nigrostriatal pathway in swine. Living dopaminergic micro-TENNs will be constructed with an
architecture consisting of a discrete population of neurons with unidirectional long-projecting axonal tracts.
Micro-TENN health, phenotype, structure, and function will be optimized in vitro. To enable clinical translation,
we will construct human-scale micro-TENNs using human stem cell derived dopaminergic neurons. Preformed
constructs will be stereotactically microinjected into neurodegenerative PD rat and pig models to assess circuit
reconstruction and motor symptom amelioration. Nigrostriatal pathway reconstruction will be assessed using
behavioral, imaging, electrophysiological, and histological outcomes. The proposed work will establish the
future clinical potential of personalized micro-TENNs to ameliorate PD motor symptoms by restoring the
dopaminergic nigrostriatal pathway. Our micro-tissue engineering strategy addresses a crucial gap in clinical
treatment by providing a means to directly replace the nigrostriatal pathway and, as a result, restore motor
function following PD neurodegeneration. By virtue of their long axonal tracts, micro-TENNs may be capable of
replacing degenerated circuitry to restore dopaminergic inputs to the striatum. Our custom process to generate
micro-TENNs enables a precisely engineered structure where the number of neurons and genera...

## Key facts

- **NIH application ID:** 9932292
- **Project number:** 5I01BX003748-04
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** Daniel Kacy Cullen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932292

## Citation

> US National Institutes of Health, RePORTER application 9932292, Transplantable Micro-Tissue Engineered Neural Networks to Restore the Nigrostriatal Pathway in Parkinson's Disease (5I01BX003748-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9932292. Licensed CC0.

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