About

Han-Chiao Isaac Chen, MD, is an Associate Professor of Neurosurgery at the Hospital of the University of Pennsylvania and the Veteran's Administration Medical Center. He serves as an Attending Neurosurgeon at multiple institutions including the Corporal Michael J Crescenz Veterans Affairs Medical Center, Penn Presbyterian Medical Center, and Pennsylvania Hospital. Dr. Chen is a member of several research and clinical centers, including the Center for Brain Injury and Repair, the Institute for Translational Medicine and Therapeutics, the Institute of Regenerative Medicine, and the Center for Neuroengineering and Therapeutics. He holds leadership roles such as Surgical Director of the Penn Epilepsy Center and Residency Program Director in the Department of Neurosurgery at the University of Pennsylvania, as well as Co-Director of the Neurodevelopment & Regeneration Program at the Institute of Regenerative Medicine. His clinical interests focus on functional neurosurgery, including epilepsy surgery and deep brain stimulation, as well as the resection of tumors in eloquent brain tissue. Dr. Chen's research centers on developing novel approaches to restore brain function, with particular emphasis on reconstructing cortical circuitry. His laboratory combines neural tissue engineering, stem cell biology, and neural interface technologies to generate structured neural and axonal tissue for transplantation. He studies the factors that promote neural tissue survival and integration in vivo and investigates the functional effects of this tissue on large-scale neuronal networks. Additionally, Dr. Chen is involved in translating central nervous system gene therapies using large-animal models.

Research topics

• Computer Science
• Cell biology
• Biology
• Anatomy
• Neuroscience

Selected publications

• Thalamus: a real-time system for synchronized, closed-loop multimodal behavioral and electrophysiological data capture

  Communications Engineering · 2026-03-26

  articleOpen access

  Precise and synchronized multimodal data capture in neurosurgical environments is essential for further understanding brain function and will be crucial to advancing the development of brain-computer interface technology. We have developed an open-source software platform named Thalamus, for multimodal data capture integrated with existing sensors and hardware commonly utilized in the operating room and other clinical environments such as pulse oximeters, inertial sensors, electromyography and neural electrophysiology. Thalamus facilitates synchronous recording of neural and behavioral data, enabling real-time computation for closed-loop experiments and detailed analysis of complex motor functions and neural activity. Thalamus uses a modular, configurable node-based pipeline with a tiered Python and C + + architecture. These design elements allow Thalamus to support a wide range of high-resolution sensors for diverse behavioral data types and enable robust closed-loop synchronization of various data streams. Validation experiments demonstrate that Thalamus is capable of data integration and concurrent analysis with up to sub-millisecond precision, offering great potential for enhancing neurosurgical research and clinical applications. By leveraging conventional sensors and hardware already in use, Thalamus supports adoption into the clinical environment, paving the way for more comprehensive, data-driven approaches to neurological care and improving the personalization and rigor of treatment strategies.

  PublisherDOI

• Next-Generation Sequencing of Intraoperatively Acquired Cerebrospinal Fluid and Matched Tumor Tissue in Patients Undergoing Surgical Resection for Glioblastoma

  JCO Precision Oncology · 2025-09-01 · 1 citations

  articleOpen access

  PURPOSE Because of tumor heterogeneity and sampling error, next-generation sequencing (NGS) of glioblastoma (GBM) tumors may provide an incomplete picture of the somatic mutational landscape. We hypothesized that simultaneous targeted NGS of matched tumor tissue and cerebrospinal fluid (CSF), obtained during craniotomy for resection of GBM, would lead to identification of clinically relevant variants not detected by tissue NGS alone. METHODS We enrolled 50 patients undergoing resection of newly diagnosed (n = 15) or recurrent (n = 35) GBM. CSF was collected intraoperatively via the subarachnoid space (n = 25) or lateral ventricle (n = 25) and assayed by NGS using a hybrid capture liquid biopsy panel. Matched tumor tissue also underwent large panel hybrid capture NGS testing. RESULTS CSF samples from 28 of 50 patients (56%) passed quality control metrics. At least one CSF variant was detected in 25 of 28 patients (89%), and 22 of 28 patients had matched tissue sequencing results available. In these 22 patients (primary analysis cohort), the median number of variants detected in CSF was higher than in tissue (3 v 2 variants, respectively; P = .0035), and 15 of 22 patients (68%) had ≥1 CSF variant not detected in matched tissue, including clinically relevant alterations in EGFR , PMS2 , PIK3CA , and TP53 . CONCLUSION The addition of intraoperatively acquired CSF liquid biopsy to tissue NGS in patients with GBM may improve detection of clinically relevant variants, potentially improving selection of patients for clinical trials.

  PublisherOA PDFDOI

• 1308 A Decade of Change: Trends and Disparities in Medicare Reimbursement for Deep Brain Stimulation

  Neurosurgery · 2025-03-14

  article

  INTRODUCTION: Deep brain stimulation (DBS) is a vital intervention for movement disorders such as Parkinson's disease, essential tremor, and dystonia. From 2013 to 2021, Medicare expenditures increased from $586 billion to $829 billion. Despite this growth, understanding the financial trends specific to DBS is crucial for ensuring its sustainability and equitable access. METHODS: A retrospective analysis of Medicare reimbursement and charges for DBS procedures from 2013 to 2021 was conducted using data from the Centers for Medicare & Medicaid Services. Statistical significance tests compared reimbursement rates between years and geographical variability in reimbursement was also analyzed. RESULTS: The analysis showed a decline in both mean charges and Medicare payments for DBS procedures. Mean charges decreased from $4,822.26 in 2013 to $4,382.21 in 2021, while mean payments declined from $960.05 to $801.47. Despite the rise in overall Medicare expenditures, the reimbursement to charges ratio remained stable at 18-20%. Significant decreases in reimbursement were found between 2013 vs. 2019 (p=0.029) and 2013 vs. 2021 (p=0.003). Geographical analysis revealed substantial inter-state variability, with reimbursement rates ranging from 8% to 56%. The total number of DBS procedures peaked in 2019 at 7,641 but declined thereafter, likely due to the COVID-19 pandemic, with a slight recovery in 2021. CONCLUSIONS: This study highlights a concerning trend of decreasing Medicare reimbursement for DBS procedures amidst rising overall Medicare expenditures. Significant regional disparities underscore the need for policy interventions to address these financial challenges. Ensuring sustainable and equitable access to DBS treatments is crucial for advancing the field and improving patient outcomes. Further research is needed to explore underlying factors and develop strategies to mitigate their impact on clinical practice.

  PublisherDOI

• Reducing artifacts during human intracranial electrical stimulation by separating current return from recording ground

  Brain stimulation · 2025-10-30

  letterOpen access

  Direct electrical stimulation is an essential tool for treating neurological and psychiatric disorders, investigating brain function, and developing brain-computer interfaces1–6. To understand the effects of electrical stimulation, it is often necessary to record neural activity before, during, and after a pulse train is delivered. However, recording useful neural data during and immediately after stimulation can be difficult because the artifacts induced by stimulation are several orders of magnitude larger than the evoked neural response.

  PublisherOA PDFDOI

• A data-driven single-cell and spatial transcriptomic map of the human prefrontal cortex

  Science · 2024-05-23 · 64 citations

  articleOpen access

  The molecular organization of the human neocortex historically has been studied in the context of its histological layers. However, emerging spatial transcriptomic technologies have enabled unbiased identification of transcriptionally defined spatial domains that move beyond classic cytoarchitecture. We used the Visium spatial gene expression platform to generate a data-driven molecular neuroanatomical atlas across the anterior-posterior axis of the human dorsolateral prefrontal cortex. Integration with paired single-nucleus RNA-sequencing data revealed distinct cell type compositions and cell-cell interactions across spatial domains. Using PsychENCODE and publicly available data, we mapped the enrichment of cell types and genes associated with neuropsychiatric disorders to discrete spatial domains.

  PublisherOA PDFDOI

• Magnetic Resonance Imaging–Guided Frameless Stereotactic Injections of the Bilateral Cerebellar Dentate Nuclei in Nonhuman Primates: Technical Note

  Operative Neurosurgery · 2024-02-01 · 2 citations

  articleSenior author

  BACKGROUND AND OBJECTIVES: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the growing promise of cell and gene therapies for the treatment of neurological diseases, it is important to ensure the accurate and safe delivery of these agents to target structures in the brain. However, a standard guideline or method has not been developed for stereotactic targeting in NHPs. In this article, we describe the safe use of a magnetic resonance imaging-guided frameless stereotactic system to target bilateral cerebellar dentate nuclei for accurate, real-time delivery of viral vector in NHPs. METHODS: Seventeen rhesus macaques (Macaca mulatta) underwent stereotactic surgery under real-time MRI guidance using the ClearPoint® system. Bilateral cerebellar dentate nuclei were targeted through a single parietal entry point with a transtentorial approach. Fifty microliters of contrast-impregnated infusate was delivered to each dentate nucleus, and adjustments were made as necessary according to real-time MRI monitoring of delivery. Perioperative clinical outcomes and postoperative volumes of distribution were recorded. RESULTS: All macaques underwent bilateral surgery successfully. Superficial pin site infection occurred in 4/17 (23.5%) subjects, which resolved with antibiotics. Two episodes of transient neurological deficit (anisocoria and unilateral weakness) were recorded, which did not require additional postoperative treatment and resolved over time. Volume of distribution of infusate achieved satisfactory coverage of target dentate nuclei, and only 1 incidence (2.9%) of cerebrospinal fluid penetration was recorded. Mean volume of distribution was 161.22 ± 39.61 mm3 (left, 173.65 ± 48.29; right, 148.80 ± 23.98). CONCLUSION: MRI-guided frameless stereotactic injection of bilateral cerebellar dentate nuclei in NHPs is safe and feasible. The use of this technique enables real-time modification of the surgical plan to achieve adequate target coverage and can be readily translated to clinical use.

  PublisherDOI

• Dopaminergic Axon Tracts Within a Hyaluronic Acid Hydrogel Encasement to Restore the Nigrostriatal Pathway

  Advanced Healthcare Materials · 2024-11-04 · 6 citations

  articleOpen access

  Parkinson's disease is characterized by motor deficits emerging from insufficient dopamine in the striatum after degeneration of dopaminergic neurons and their long-projecting axons comprising the nigrostriatal pathway. To address this, a tissue-engineered nigrostriatal pathway (TE-NSP) featuring a tubular hydrogel with a collagen/laminin core that encases aggregated dopaminergic neurons and their axonal tracts is developed. This engineered microtissue can be implanted to replace neurons and axons with fidelity to the lost pathway and thus may provide dopamine according to feedback from host circuitry. While TE-NSPs have traditionally been fabricated with agarose, here a hyaluronic acid (HA) hydrogel is utilized to have a more bioactive encasement while expanding control over physical and biochemical properties. Using rat ventral midbrain neurons, it is found that TE-NSPs exhibited improved neurite growth with HA relative to agarose, with no differences in electrically-evoked dopamine release. When transplanted, HA hydrogels reduced average host neuron loss and inflammation around the implant compared to agarose, and TE-NSP neurons and axonal tracts survived for at least 2 weeks to structurally emulate the lost pathway. This study represents an innovative use of HA hydrogels for neuroregenerative medicine and enables future studies expanding the control and functionality of TE-NSPs.

  PublisherOA PDFDOI

• Temporal multi-modal single-cell analyses reveal dynamic interactions of CAR-T cells with glioblastoma and targeting of antigen-negative neoplastic cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-04 · 2 citations

  preprintOpen access

  SUMMARY CAR-T therapy is a promising new immunotherapy for cancers, but its efficacy for solid tumors requires improvement. A detailed understanding of the interplay between solid tumors and CAR-T cells is critical. Here we report temporal, multi-modal, single-cell profiling of patient-derived glioblastoma organoids with CAR-T treatment. We found that all tumor cell types responded to CAR-T cell activation and contributed to an initially anti-tumor, but subsequently pro-tumor and immune-inhibitory microenvironment, accompanied by CAR-T cell exhaustion. Unexpectedly, CAR-T treatment attenuated glioma stem-like states of both antigen-positive and antigen-negative neoplastic cells and reduced their proliferation via diffusible factors, including IFNγ. Analysis of samples from additional patients, including those in clinical trials, supported these findings. Our study reveals the dynamic interplay among different tumor cells and T cells in adaptive responses to immunotherapy and identifies previously unappreciated benefits of CAR-T therapy directly on antigen-negative neoplastic cells that may be leveraged to enhance therapeutic efficacy.

  PublisherDOI

• Return of intracranial beta oscillations and traveling waves with recovery from traumatic brain injury

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-07-23 · 2 citations

  preprintOpen access

  Traumatic brain injury (TBI) remains a pervasive clinical problem associated with significant morbidity and mortality. However, TBI remains clinically and biophysically ill-defined, and prognosis remains difficult even with the standardization of clinical guidelines and advent of multimodality monitoring. Here we leverage a unique data set from TBI patients implanted with either intracranial strip electrodes during craniotomy or quad-lumen intracranial bolts with depth electrodes as part of routine clinical practice. By extracting spectral profiles of this data, we found that the presence of narrow-band oscillatory activity in the beta band (12-30 Hz) closely corresponds with the neurological exam as quantified with the standard Glasgow Coma Scale (GCS). Further, beta oscillations were distributed over the cortical surface as traveling waves, and the evolution of these waves corresponded to recovery from coma, consistent with the putative role of waves in perception and cognitive activity. We consequently propose that beta oscillations and traveling waves are potential biomarkers of recovery from TBI. In a broader sense, our findings suggest that emergence from coma results from recovery of thalamo-cortical interactions that coordinate cortical beta rhythms.

  PublisherOA PDFDOI

• Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson’s Disease and Cortical Injury

  Brain Sciences · 2023-11-29 · 9 citations

  articleOpen accessSenior authorCorresponding

  Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through "bystander effects" and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson's disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson's disease as well as the use of structured grafts such as brain organoids for cortical repair.

  PublisherOA PDFDOI

Recent grants

• NIH Grant F32NS073267

  NIH · $98k · 2013

• Chronic Versus Acute Transplantation of Neural Tissues for TBI-Induced Cortical Injuries

  NIH · $2.0M · 2021–2026

• Designing Neural Tissue Constructs that Mimic Brain-Specific Architecture

  NIH · 2016–2021

Frequent coauthors

• D. Kacy Cullen

  63 shared

• John A. Wolf

  University of Pennsylvania

  55 shared

• Hongjun Song

  27 shared

• Guo‐li Ming

  27 shared

• Kevin D. Browne

  University of Pennsylvania

  24 shared

• Laura A. Struzyna

  University of Pennsylvania

  20 shared

• Douglas H. Smith

  University of Pennsylvania

  17 shared

• Justin C. Burrell

  University of Pennsylvania

  17 shared

Labs

• Chen LaboratoryPI