Graeme F. Woodworth, MD, B.S.

McGirt MJ, Woodworth GF, Coon AC, Thomas G, Williams M, Rigamonti D. Diagnosis, treatment, and analysis of long-term outcomes in idiopathic normal pressure hydrocephalus. Neurosurgery, 2005, 57: 699-705.

Woodworth GF, Chaichana K, McGirt MJ, Sciubba D, Gokaslan Z.  Predictors of ambulatory status following resection of intramedullary spinal cords tumors. Neurosurgery, 2007 61: 99-105

Woodworth GF, McGirt  MJ, Huang J, Perler B, Clatterbuck RC, Tamargo RJ. Selective versus Routine Intraoperative Shunting during Carotid Endarterectomy: A Multivariate outcome analysis. Neurosurgery, 2007, 61: 1170-6.

Link T, Woodworth GF, Chaichana KL, Mayer SA, Grossman RS, Quinones-Hinojosa A.  Hyperglycemia is independently associated with post-operative function loss in primary glioblastoma. J Clin Neurosci., 2012, 19: 996-1000. (PMCID: 4859215)

McGirt MJ, Woodworth GF, Frazier JM, Coon AL, Olivi A, Weingart JD. Independent predictors of morbidity after image-guided stereotactic brain biopsy: A risk assessment of 270 cases. J Neurosurgery, 2005, 102: 897-901.

Woodworth GF, McGirt MJ, Samdani A, Garonzik I, Olivi A, Weingart JD. Accuracy of frameless and frame-based MRI-guided stereotactic brain biopsy in the diagnosis of glioma: Comparison of biopsy and open resection specimen.  Neurological Research, 2005 27: 358-62.

Woodworth GF, McGirt MJ, Samdani A, Garonzik I, Olivi A, Weingart JD. Frameless image-guided stereotactic brain biopsy: Diagnostic yield, operative morbidity, and comparison with the frame-based technique. J Neurosurgery, 2006, 104: 233-7

Woodworth GF, Garzon-Muvdi T, Blakeley JO, Yu X, Weingart J & Burger PC, Histo-pathological correlates with survival in re-operated glioblastoma. J Neurooncol. 2013, 113: 485-93.

Nance EA, Timble K, Miller, W, Song J, Louttit C, Klibanov A, Shih T, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ. Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J. Cont. Release, 2014, 189: 123-32. Received the Jorge Heller Outstanding Paper Award, Controlled Release Society 2015 (PMCID: 4125545)

Kim AJ, Woodworth GF*, Boylan NJ, Suk JS, Hanes J*. Highly compacted pH-responsive DNA nanoparticles mediate transgene silencing in experimental glioma. J. Mat. Chem. B 2014, 2: 8165-8173. (* corresponding author) (PMCID: 4254827)

Nance EA*, Woodworth GF*, Sailor K, Tamargo RJ, Eberhart CE, Hanes J. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Science Translational Medicine, 2012, 4(149):149ra119. [* co-first authors]  (PMCID: 3718558)

Woodworth GF, Garzon-Muvdi T, Blakeley JO, Yu X, Weingart J & Burger PC, Histo-pathological correlates with survival in re-operated glioblastoma. J Neurooncol. 2013, 113: 485-93. (PMCID: 3994532)

Mastorakos P, Zhang C, Berry S, Oh Y, Lee S, Eberhart CG, Woodworth GF, Suk JS, Hanes J. Highly PEGylated DNA nanoparticles provide uniform and widespread gene transfer in the brain. Adv Healthcare Mater. 2015, 4: 1023-1033. (PMCID: 4433405)

Hersh DS, Houbova P, Castellani RJ, Rodriguez FJ, Mehta MP, Woodworth GF. Pathologic deposition of non-amyloid immunoglobulin in the brain leading to mass effect and neurological deficits. J Clin Neurosci. 2016 Mar 4. PMID: 26954763

Perez J, Tran N, Rosenblum M, Schneider C, Connolly N, Kim AJ, Woodworth GF, Winkles JA. The TWEAK receptor Fn14 is a potential cell surface portal for targeted gelivery of glioblastoma therapeutics. Oncogene 2016, 35: 2145-2155. (PMCID: 4850525)

Research Themes:

Development of therapeutic ultrasound methods for brain cancer.

Our work is investigating the interstitial, immunological, and blood vessel effects created in the brain and brain tumors following treatment with pulsed focused ultrasound, with the goal of identifying safety thresholds, biological alterations, and therapeutic delivery enhancements. These efforts have included image-guided thermal, and microbubble-enhanced ultrasound regimes to influence the brain extracellular space, neuro-vascular unit, and immune responses.

We have identified ultrasound parameters to safely expand the pores within the brain interstitium and are studying the effects of these changes on drug and particle distribution, neuronal function, clearance pathways, and antigen presentation. The long-term goals of this work are to define the value of therapeutic ultrasound and ultrasound-enhanced therapeutics for brain cancers.

1. Nance EA, Timble K, Miller, W, Song J, Louttit C, Klibanov A, Shih T, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ. Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J. Cont. Release, 2014, 189: 123-32. (PMCID: 4125545)
2. Hersh DS, Nguyen BA, Dancy JG, Adapa AR, Winkles JA, Woodworth GF, Kim AJ, Frenkel V. Pulsed ultrasound expands the extracellular and perivascular spaces of the brain. Brain Res., 2016, Jun 28. pii: S0006-8993(16)30464-4. (PMID: 27369449)
3. Hersh DS, Anastasiadis P, Mohammadabadi A, Nguyen BA, Guo S, Winkles JA, Kim AJ, Gullapalli R, Keller A, Frenkel V, Woodworth GF. MR-guided transcranial focused ultrasound safely enhances interstitial dispersion of large polymeric nanoparticles in the living brain. PLoS ONE 2018 13(2): e0192240. (PMID: 29415084)

Genetically-engineered models of human brain cancer.

Our team has extended the suite of genetically engineered (GE) models of human glioma by developing the first transgenic rat that leverages the RCAS/tv-a system originally developed for the mouse. This rat model has enabled comparative oncology and translational therapeutic studies, including focused ultrasound and local delivery approaches. Specifically, we are evaluating the interstitial effects and improvement in drug delivery using therapeutic ultrasound regimes. We are also investigating the biological overlap and deviation within mammalian forms of glioma (mouse, rat, canine, and human), to better understand the conserved and species-specific gene expression and signaling networks.

A fundamental aspect of all gliomas is the requirement for tumor initiation and progression in the central nervous system, with rare evidence of metastasis or growth elsewhere in the body. This biological feature strongly implicates the tumor-host microenvironment and local immunological escape in the disease pathogenesis. The information derived from these studies and models has important implications for preclinical models of human glioma and predictive therapeutic testing.

1. Connolly NP, Stokum JA, Schneider CS, Ozawa T, Xu S, Galisteo R, Castellani RJ, Kim AJ, Simard JM, Winkles JA, Holland EC, Woodworth GF. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer.  PLoS One. 2017 Mar 30;12(3). (PMID: 28358926)
2. Connolly NP, Shetty AC, Stokum JA, Hoeschele I, Siegel MB, Miller CR, Kim AJ, Ho C, Davila E, Simard JM, Devine SE Rossmeisl JH, Holland EC, Winkles JA, Woodworth GF. Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma. Sci Rep. 2018 Jan 19;8(1):1180. (PMID: 29352201)

Advanced nanomedicine formulations for treating invasive brain cancer.

Our team has developed polymeric drug formulations that provide controlled release, enhanced tissue penetration, and structure specific targeting in the brain. These formulations offer the potential to significantly improve the therapeutic effects while minimizing off-target toxicities and side effects of numerous otherwise ineffective or toxic drugs.

Early studies using these nano-drug formulations have demonstrated improvements in nanoparticle retention, drug potency and duration of effects, and safety in vivo compared to free drug and other polymeric formulations. Recent studies have focused on Fn14 targeted versions that maintain brain penetrating properties. Our team has led the engineering, characterization, and testing of these advanced nanoparticle formulations.

1. Nance EA*, Woodworth GF*, Sailor K, Tamargo RJ, Eberhart CE, Hanes J. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Science Translational Medicine, 2012, 4(149):149ra119. [* co-first authors] (PMCID: 3718558)
2. Schneider CS, Perez-Bermudez J, Cheng E, Smith P, Winkles JA, Woodworth GF*, Kim AJ*. Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells. Biomaterials, 2015, 42:42-51. (*co-corresponding authors). Received the Jorge Heller Outstanding Paper Award, Controlled Release Society 2015 (PMCID: 4279109)
3. Dancy JG, Wadajkar AS, Schneider CS, Mauban JR, Goloubeva OG, Woodworth GF, Winkles JA, Kim AJ. Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue. J Control Release. 2016, 238: 139-148. (PMID: 27460683)
4. Wadajkar AS, Dancy JG, Roberts NB, Connolly NP, Strickland DK, Winkles JA, Woodworth GF, Kim AJ. Decreased non-specific adhesivity Receptor Targeted (DaRT) nanoparticles improve dispersion, cellular uptake, and tumor retention in invasive gliomas. J Control Release. 2017 Sep 5. pii: S0168-3659(17)30829-5. (PMID: 28887134)

Studies to improve the safety and accuracy of neurosurgical treatments.

Using retrospective and prospective patient outcomes registries, this work has systemically evaluated neurosurgical treatments and patient outcomes. These studies have helped to create a framework to utilize the operating room as an adjunct to basic and translational research. Trial and error, and word of mouth advancement has typified much of the history of modern surgical training and adoption of surgical techniques, while the use of randomized controlled surgical trials has been challenging due to inherent biases and ethical considerations.

For these reasons, surgical outcomes registries have proven useful for enabling valuable analyses of treatment outcomes and guiding improvements in patient care. The results of this work have offered new insights into the clinical management of patients with hydrocephalus, cerebrovascular disease, and brain and spinal tumors.

1. Woodworth GF, McGirt MJ, Samdani A, Garonzik I, Olivi A, Weingart JD. Accuracy of frameless and frame-based MRI-guided stereotactic brain biopsy in the diagnosis of glioma: Comparison of biopsy and open resection specimen. Neurological Research, 2005 27: 358-62.
2. Woodworth GF, McGirt MJ, Samdani A, Garonzik I, Olivi A, Weingart JD. Frameless image-guided stereotactic brain biopsy: Diagnostic yield, operative morbidity, and comparison with the frame-based technique. J Neurosurgery, 2006, 104: 233-7.
3. Woodworth GF, McGirt MJ, Huang J, Perler B, Clatterbuck RC, Tamargo RJ. Selective versus Routine Intraoperative Shunting during Carotid Endarterectomy: A Multivariate outcome analysis. Neurosurgery, 2007, 61: 1170-6.
4. Woodworth GF, McGirt MJ, Williams MA, Rigamonti D. Cerebral spinal fluid drainage and dynamics in the diagnosis of normal pressure hydrocephalus. Neurosurgery, 2009; 64: 919-25; discussion 925-6. Editor’s Choice. (PMID: 19404152)

• Diplomate, American Board of Neurological Surgeons
• Fellow, American Association of Neurological Surgeons
• Fellow, American College of Surgeons

2004          Clinical Research Award, Southern Society of Neurological Surgery Annual Meeting

2004          Medical Student Research Award, Alpha Omega Alpha Honors Society

2004          B. Wood Research Award, Johns Hopkins School of Medicine

2007          Patient Safety Research Award, Johns Hopkins Department of Neurosurgery

2009          T32 Award, Nanotechnology in Cancer Medicine, Johns Hopkins University

2009          Top Ten Abstract, CNS Annual Meeting, New Orleans, Louisiana

2010          Chairman’s Award for Patient Safety Research, Johns Hopkins Department of Neurosurgery

2011          Harvey Cushing Research Award, Johns Hopkins Department of Neurosurgery

2012          Neurosurgeon Research Career Development Program Award, Massachusetts General Hospital/NINDS

2013          Clinician-Scientist Award, The Passano Foundation

2014          Dean’s Challenge Award, University of Maryland School of Medicine

2014          Pilot Research Award, Greenebaum NCI Cancer Center, University of Maryland

2015          Innovation in Biotechnology Award, (co-awardee) American Association of Pharmaceutical Scientists and Genentech

2015          Jorge Heller Outstanding Paper Award, (co-awardee) Controlled Release Society

2016          Research Scholar Award, American Cancer Society

2017          Pilot Research Award, University of Maryland Greenebaum Comprehensive Cancer Center

2018          Accelerated Translational Project Award, Institute for Clinical and Translational Research, University of Maryland School of Medicine

2018          University of Maryland Research and Innovation Award – M-Power Program

2019          Andrew J. Lockhart Memorial Prize, Focused Ultrasound Foundation

2019          Top Docs, Baltimore Magazine

RSG-16-012-01-CDD (PI: Woodworth) 07/01/16-06/30/20

American Cancer Society
Fn14-targeted biodegradable BCNU-loaded nanoparticles for invasive brain cancer

The goal of this proposal is to study and engineer nanoparticle technologies to improve the delivery of the chemotherapy BCNU beyond that achieved by interstitial polymeric wafers.

MPower Award (mPI: Woodworth, Huang, Chen) 01/01/19-12/30/21

University of Marylan
Image-guided photodynamic priming to prevent brain tumor recurrence

This project is studying photodynamic activation of the glioma microenvironment to enhance therapeutic delivery and associated effects

R01 NS107813 (PI: Woodworth) 04/01/19-03/31/24

NIH/NIND
Nanotherapeutic treatment of the invasive glioblastoma microenvironment

This project will explore the role of Fn14 in the patho-biology and therapeutic targeting of the invasive components of GBM.

R21 NS113016 (mPI: Woodworth, Bettegowda) 07/01/19-06/302021

NIH/NINDS
MRgFUS-enabled non-invasive interrogation of malignant glioma via circulating tumor DNA

This project will investigate if circulating levels of brain tumor DNA can be detected after blood brain barrier disruption via MRI-guided focused ultrasound.

Maryland Innovation Initiative (mPI: Kim, Woodworth, Winkles) 08/01/19-07/31/20

Technology Assessment Program
Development of the DART therapeutic nanoparticle platform for Fn14-positive cancers

This product development award through the State of Maryland TEDCO program brings together industry experts and university-based scientists to promote commercialization of promising new technologies.

NCT03322813 07/01/18-06/30/20

InSightec, BT004
“ExAblate Blood Brain Barrier Disruption (BBBD) for Planned Surgery in Glioblastoma”

This Phase 0 study is designed to assess the safety and feasibility of using the ExAblate, Type 2 to temporarily disrupt the blood brain barrier in non-enhancing suspected glioblastomas. The ExAblate Model 4000 Type-2 is intended for use as a tool to disrupt the BBB.

NCT03551249 07/01/18-06/30/20

InSightec, BT008
“Assessment of Safety and Feasibility of ExAblate Blood-Brain Barrier Disruption for the Treatment
of High Grade Glioma in Patients Undergoing Standard Chemotherapy”

This Phase 0 study is designed to assess the safety and feasibility of using the ExAblate, Type 2 to temporarily disrupt the blood brain barrier in the setting of standard maintenance chemotherapy for primary glioblastoma, temozolomide. The ExAblate Model 4000 Type-2 is intended for use as a tool to disrupt the BBB.