MICA: Convection-enhanced delivery of encapsulated nanospheres for controlled delivery of chemotherapy to the brain

Lead Research Organisation: University of Bristol
Department Name: Clinical Science at North Bristol

Abstract

Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumour. Despite advances in chemotherapy, radiotherapy and surgical technology, the prognosis remains poor. Only a minority of patients are suitable for maximal treatment comprising surgical excision, radiotherapy and chemotherapy, and even following maximal treatment, average survival remains at approximately 14 months from diagnosis. There is no cure for GBM and patients inevitably suffer from recurrence and progression of the disease. The majority of tumour recurrences occur within 2cm of the site of the original tumour due to microscopic invasion of tumour cells into surrounding brain tissue which escape surgical excision and radiotherapy.

One of the major obstacles to the effective treatment of brain tumours is the existence of the blood-brain barrier (BBB), which prevents the free passage of drugs from the bloodstream into the brain. It is sometimes possible to increase the amount of drug which enters the brain by using high drug doses, but this often results in severe side-effects which are unacceptable to patients.

Our solution is to bypass the BBB by delivering chemotherapy directly to brain tissue surrounding the tumour following excision, using a neurosurgical technique called convection-enhanced delivery (CED). CED describes a method of direct drug delivery to the brain through ultrafine microcatheters. This technique allows us to target the chemotherapy to recurrent brain tumours with very high safety and accuracy, and to distribute effective drug concentrations throughout relevant areas of the brain. This approach also reduces the risk of side-effects by specifically targetting drugs to the brain. We have previously used this technique to deliver drugs to patients with Parkinson's Disease, and over the last 5 years we have been working with industrial collaborators to develop a CED catheter system which allows us to deliver repeated drug doses to the brain.

In this project we propose to combine CED with recent advances in the field of nanotechnology. By encapsulating chemotherapies in biodegradable nanospheres our aim is to achieve controlled drug release within the brain, to reduce the drug doses required to achieve tumour regression, and to limit the risk of side-effects. We have chosen a nanosphere formulation which is widely used in the medical industry and is proven to be safe and non-toxic. We have approval for a clinical trial of CED of unencapsulated chemotherapy, and this study represents a logical progression. By using CED to deliver chemotherapy nanoparticles to the brain we hope to reduce tumour recurrence and progression and to improve the quality of life of patients with this devastating disease.

Our research team comprises a unique collaboration between neurosurgeons, neuroscientists, chemists and chemical engineers with the knowledge and experience to develop this novel technology for patient benefit.

Technical Summary

Our aim is to formulate biodegradable polymer-encapsulated carboplatin nanospheres suitable for convection-enhanced delivery (CED) for the treatment of recurrent/progressive Glioblastoma multiforme. The size and charge of nanospheres will be analysed using electron microscopy, dynamic light scattering and a particle zetasizer. Drug loading, size, charge and drug release profile will be optimised by manipulating such parameters as the polymer composition, synthesis conditions and extent of surface hydrolysis.

The structure and associated drug release of nanospheres will be analysed in artificial cerebrospinal fluid, PBS and saline using atomic absorption spectroscopy (AAS), and nuclear magnetic resonance (NMR) relaxometry and cryoporometry. The cytotoxic efficacy of carboplatin nanospheres will be compared to unencapsulated carboplatin in human glioma and neuronal cultures. This will allow us to select the optimum formulation and vehicle for in vivo testing of CED of nanospheres.

The distribution, half-life and toxicity of nanospheres delivered by CED will be studied in vivo. Catheters will be stereotactically inserted into the brain and distribution analysed using fluorescently-labelled nanospheres. The in vivo clearance, half-life and stability of platinum released from nanospheres will be assessed using AAS and liquid chromatography-mass spectrometry. The toxicity of chemotherapy nanospheres will be compared to unencapsulated carboplatin by analysing the extent of astrocytosis, pre-and post-synaptic proteins and neuronal content.

On the basis of in vitro testing of loading efficiency, charge, size and drug release profile as well as in vivo analysis of distribution, half-life and toxicity in a small animal model we will progress to in vivo testing in a large animal model. We will perform intermittent drug delivery at intervals determined by clearance studies using a chronic in-dwelling CED catheter system in order to complete a dose-escalation study

Planned Impact

The outcomes of this research project are likely to have a number of economic and societal implications resulting in a number of non-academic beneficiaries both in the short and long-term.

Short-term beneficiaries:
1. The pharmaceutical industry
One of the major aims of this study is to combine advances in convection-enhanced drug delivery technology with the use of nanoformulations. Such a treatment strategy has applications for a range of neuro-therapeutics. We envisage that a successful outcome in this study will attract R&D investment from the pharmaceutical industry which will facilitate rapid translation to clinical trials. The Functional Neurosurgery Research Group has on-going collaborations with a number of US and European pharmaceutical biotechnology companies who also stand to benefit from success in this study. A second major aim is the development of a biocompatible nanoscale drug delivery platform which facilitates controlled drug release over a prolonged period. Such a system has applications for a range of therapeutic agents.

2. UK medical device and nanotechnology regulators
The Medical and Healthcare Regulatory Agency (MHRA) has been actively involved in aiding our research group to obtain approval for clinical trials of CED for both neuro-oncological and neurodegenerative disorders. The MHRA is also committed to monitoring the progress of nanotechnology in healthcare. Successful outcomes from this study and rapid progression to subsequent clinical trials could provide a model for safe and effective translational research in the rapidly expanding field of nanomedicine.

3. Renishaw Plc. (Industrial Collaborators)
The chronic intermittent catheter systems described in this proposal are manufactured by our industrial collaborators. This study has the potential to validate use of this device for chronic intermittent delivery of nanoparticles. Industrial collaboration is paramount for effective translation of this therapeutic strategy to clinical trials, for large-scale production of catheter systems and for collaboration with the pharmaceutical industry. Success in this study is likely to attract further R&D investment from pharmaceutical collaborators and to promote the sustainability of the business, in particular, Renishaw's Neurological Products Division.

4. The general public
Successful results relating to the safety and toxicity of the nanoformulations used in this study are likely to increase public confidence in emerging nanotechnologies and their application to nanomedicine. We plan to contribute to the debate by providing scientifically rigorous content for websites, the press and public science events.

Longer-term beneficiaries:
5. Patients with recurrent/progressive Glioblastoma Multiforme.
The ultimate aim of this research is to facilitate a phase I clinical trial of convection-enhanced delivery of biodegradable polymer-encapsulated carboplatin nanospheres for recurrent/progressive GBM. By delivering the therapeutic agent to peritumoral tissue our aim is to target invasive tumour cells which escape surgical resection and the field of radiotherapy, and thereby reduce the risk of tumour recurrence/progression. By encapsulating chemotherapy in polymeric nanospheres our aim is to reduce the overall dose required and the frequency of dosing, reduce side-effects and also the development of resistance to chemotherapy.

6. The National Health Service
By encapsulating chemotherapy within nanospheres we aim to achieve prolonged drug release within the brain, and thereby reduce the frequency of drug administration without impairing clinical efficacy. The chronic intermittent drug delivery system is designed to allow patients to receive drug infusions on a day case basis, which we envisage will prevent the need for inpatient admission. The reduced requirement for hospital attendance may reduce NHS in patient costs and will also improve our patients' quality of life.

Publications

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Lewis O (2016) Chronic, intermittent convection-enhanced delivery devices. in Journal of neuroscience methods

 
Description Milestone Meetings
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description MRC MR/J005134/1. Convection-enhanced delivery of encapsulated nanosperes for controlled delivery of chemotherapy to the brain
Amount £800,000 (GBP)
Funding ID MR/J005134/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2011 
End 11/2013
 
Title AAS 
Description Development /collaboration to analyze samples to enable improvements to be made for the nanoparticles prior to in vivo testing 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2012 
Provided To Others? Yes  
Impact Quantitative data sampling 
 
Title ICP-MS 
Description Inductively coupled plasma mass spectrometry (ICP-MS) is a type of mass spectrometry which is capable of detecting metals and several non-metals at concentrations as low as one part in 1012 (part per trillion). Used .for ongoing projects in collaboration with Sheffield university 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Excellent quantitative results obtained. 
 
Title LA-ICP-MS 
Description Laser Detection for ongoing projects in collaboration with Sheffield university 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Excellent detection of Carboplatin, involved in this research 
 
Description GDNF Pre-clinical and Phase II trials 
Organisation MedGenesis Therapeutix
Country Canada 
Sector Private 
PI Contribution Research partner
Collaborator Contribution The purpose of this study is to establish the optimum concentration of infused GDNF to achieve synaptogenesis and axonal sprouting (markers of neurorestoration) and to quantify the biological half-life of GDNF to determine an appropriate dosing frequency.
Impact publication and knowledge to be carried forward in the upcoming clinical trial
Start Year 2011
 
Description Surgical Equipment 
Organisation Renishaw PLC
Country United Kingdom 
Sector Private 
PI Contribution We have evaluated their drug delivery equipment in large animal models.
Collaborator Contribution Renishaw have provided stereotactic surgical equipment that have allowed us to undertake experiments in large animals.
Impact Collaboration with medical engineering company to develop drug delivery equipment for use in humans.
Start Year 2006
 
Description University of Bath 
Organisation University of Bath
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution MRC grant subcontract to supply /formulate nanocomplexes
Collaborator Contribution Chemical knowledge in formulation of nanoparticles
Impact Ongoing reached milesone one at present, now onwards to the next milestone
Start Year 2011
 
Description University of Notttingham 
Organisation University of Nottingham
Department School of Chemistry Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Specialised techniques and expertise from the team in Chemistry has allowed a sucesful collaboration
Collaborator Contribution In collaboration we have achieved milestone one and improvements can be made to the drug release profile to continue the project.
Impact Improved drug release profile to continue the project.
Start Year 2011
 
Title Patent Filed Ref P117522GB - Your ref: CED 
Description Glioblastoma is an untreatable from of brain tumour. Treatment by surgery or chemotherapy fails to prevent tumour recurrence and progression, leading to inevitable death. Previous studies have demonstrated that the majority of recurrences occur within 2cm of the original tumour site, indicating that the major cause of recurrence is microscopic tumour invasion into peritumoral brain tissue. The unmet need addressed by this invention is to target encapsulated chemotherapy nanospheres to peritumoral brain tissue in order to reduce the incidence of tumour recurrence and to prolong disease-free survival This invention builds upon extensive experience at NBT / UoB in Convection Enhanced Delivery (CED). CED is a means of delivering controlled quantities of drug directly into the brain using in-dwelling catheters and carefully controlled concentration / pressure gradients. This methodology has been developed over the past 10 years by Professor Stephan Gill in collaboration with Renishaw Plc. His team are currently treating malignant brain tumours in adult and paediatric patients with CED of carboplatin. This treatment strategy is based upon substantial pre-clinical and clinical data suggesting carboplatin directly delivered to brain tumours could be effective in controlling disease progression. However, CED of free carboplatin has a number of limitations that the current invention seeks to overcome. These include: - Carboplatin is not specifically toxic to tumour cells and could therefore result in neurotoxicity - Carboplatin is cleared from the brain relatively quickly following CED. Consequently it is necessary to perform repeat infusions over 2 to 3 days in order to maintain exposure of the tumour to therapeutic drug concentrations. Over the past 15 months the team have been working in collaboration with the Universities of Bath and Nottingham to develop and test the encapsulation of carboplatin in Polylactide-co-glycolide (PLGA) nanospheres / nanoparticles, with the specific aim of addressing the above limitations. PLGA is an FDA-approved biodegradable and biocompatible co-polymer used widely in the pharmaceutical industry. Through CED pilot studies the team have been able to devised a number of criteria in relation to nanosphere formulation and characteristics with the aim of developing carboplatin/PLGA nanospheres optimised for CED. To the best of our knowledge this is the first time carboplatin/PLGA nanospheres have been formulated specifically for delivery by CED for the treatment of brain tumours. In summary, the invention is a specific formulation of carboplatin/PLGA therapy for use in combination with CED for the treatment of brain tumours. 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2013
Licensed No
Impact The potential impact on covering our novel aspect, data generated from this grant application
 
Title CED for the treatment of Oncology and Neuro degenerative disease 
Description The knowledge gained from the Profesor Steven Gill research and clinical teams here at Bristol has allowed the successful development of Catheters in collaboration with Renishaws for the upcoming clinical trials 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Future treatment will become less invasive 
 
Description Conference nano tek 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Excellent reception to our data presented

A number of collaborators were gained after this conference
Year(s) Of Engagement Activity 2013
URL http://nanotechnology2014.conferenceseries.net/cfa.php
 
Description International Symposium on Neural Transplantation 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact • 12th International Symposium on Neural Transplantation
o Key note speaker GDNF -Back in the clinic
o Held in Cardiff, Wales.UK
o 3rd-6th September 2013



Sharing knowledge with fellow peers
Year(s) Of Engagement Activity 2013
 
Description (2015) Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Amsterdam, April 2015 SIOPE HGG/DIPG business meeting,
A phase I/II dose-escalation study of intermittent convection-enhanced delivery of carboplatin and topotecan for diffuse intrinsic pontine glioma (DIPG) in children and young adults:
Year(s) Of Engagement Activity 2015
URL http://www.dkfz.de/de/aktuelles/download/HeidelbergSIOP-BTG-Program-V8-SMP-rutk-18-05-15.pdf
 
Description (2015) Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Annual Congress of International Drug Discovery Science & Technology -)
Year(s) Of Engagement Activity 2014
URL http://www.iddst.com/iddst2014/price.asp
 
Description (2015) Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact November 2015 Texas USA Clinical Experience with an Intermittent Drug Delivery Device
Year(s) Of Engagement Activity 2015
URL http://www.soc-neuro-onc.org/cns-therapeutic-delivery-conference/
 
Description 3rd Targeted Drug Delivery for Pain and Neurologic Disease 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact • The 3rd Targeted Drug Delivery for Pain and Neurologic Disease SSG
o Speaker
o Held in San Francisco, CA. USA
o May 3 - 5, 2013

I gave a talk about the upcoming clinical trials
Year(s) Of Engagement Activity 2013
 
Description Childrens Cancer and Leukaemia Group - Radiation Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact • Childrens Cancer and Leukaemia Group - Radiation Meeting
o Speaker
o Bristol
o June 2013


Meeting and forming collaborations
Year(s) Of Engagement Activity 2013
 
Description Conference (Milan) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Conference SIOP European Society for Paediatric Oncology November 21-26 2016
Working group Meeting to include international experts in the field. Focus on biospy in DIPG and the future for research.
Year(s) Of Engagement Activity 2016
URL https://www.siope.eu/wp-content/uploads/2014/03/20160930_PreliminaryAGENDA_Milano_SIOPE-HGG_DIPG-Wor...
 
Description Conference (2015) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact February 2015
Development of a stable platform for Convection- Enhanced Delivery of chemotherapy for Glioma. III Memorial "Alicia Pueyo" DIPG Workshop, Barcelona
Year(s) Of Engagement Activity 2015
 
Description Conference (London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Drug Delivery in Paediatric Brain Tumours Conference
The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood-brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared.

Keywords: Drug delivery, translational medicine, paediatrics, brain tumours, glioma, medulloblastoma, CNS involvement, blood-brain barrier
Year(s) Of Engagement Activity 2016
URL http://ecancer.org/conference/articles/831-drug-delivery-in-paediatric-brain-tumours.php
 
Description Conference British NeuroOncology Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Conference stimulated around our poster presentations and presentation

Interest and potential collaboration was gathered
Year(s) Of Engagement Activity 2014
URL http://www.bnos.org.uk/conference.html
 
Description Developing an Auto-pilot for Functional Neurosurgery 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Developing an Auto-pilot for Functional Neurosurgery 18/10/13

Excellent group session for those that attended
Year(s) Of Engagement Activity 2013
 
Description Dutch Childhood Oncology Group and Adult Drug Delivery Symposium 15th May 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dutch Childhood Oncology Group and Adult Drug Delivery Symposium 15th May
Year(s) Of Engagement Activity 2017
 
Description First Hammer Out Patient/Carer Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact I gave a talk to patients and carers of patients with primary brain tumours regarding our research into new techniques and treatments for brain tumours.

Nil.
Year(s) Of Engagement Activity 2008,2012
 
Description Functional Neurosurgery in Bristol 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Presnentation of CED to fellow surgeons

Fellow functional neurosurgeons
Year(s) Of Engagement Activity 2011
 
Description Image guided surgery for Orthopaedic surgeons/. Medtronic 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact • Image guided surgery for Orthopaedic surgeons/. Medtronic SSG
o Speaker
o Held in Edinburgh, Scotland.UK
o 16th 17th June 2013


Technology sharing exercise
Year(s) Of Engagement Activity 2013
 
Description Local News (2013) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact A pilot into the treatment of Parkinson's disease which researchers hope could help to slow down the condition is taking place in Bristol.

Updating on sucess
Year(s) Of Engagement Activity 2013
URL http://www.bbc.co.uk/news/uk-england-bristol-24456415
 
Description Mending Brains with Parkinson's Disease 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Local Charity event to raise the profile and fund raise for the upcoming clinical trials
Year(s) Of Engagement Activity 2013
 
Description Mini-Symposium on Drug Delivery to the Brain - FDA - Washington 19th December 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Mini-Symposium on Drug Delivery to the Brain
Year(s) Of Engagement Activity 2017
 
Description Nanotechnologies in Cancer Diagnosis, Therapy and Preventions 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact • Nanotechnologies in Cancer Diagnosis, Therapy and Preventions AA
o Poster
o Held in New York
o June 11-13, 2013


Excellent networking potential for members of my research group
Year(s) Of Engagement Activity 2013
 
Description Sky News (2013) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview with SKY news

Scientists in Bristol have developed a system of tubes and catheters that allows them to pump protein therapy deep into patients' brains.
Year(s) Of Engagement Activity 2013
URL http://news.sky.com/story/1153456/brain-implant-could-stop-parkinsons-growth
 
Description Society for CNS Interstitial Delivery of Therapeutics (SCIDOT) Meeting San Francisco 15th/16th November 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Society for Neuro-Oncology (SNO) and the Society for CNS Interstitial Delivery of Therapeutics (SCIDOT) invite you to attend the 2017 SNO-SCIDOT Joint Conference on Therapeutic Delivery to the CNS which will be held on November 15-16, 2017 at the Marriott Marquis Hotel in San Francisco, California (in conjunction with the SNO Annual Meeting).



The conference organizers will include abstract presentations of original research on the interstitial delivery of therapeutics to the CNS selected from the following categories:

BBB Physiology and Barriers to CNS drug distribution
Pharmacokinetics and pharmacodynamics of CNS therapeutics
Methods for evaluating drug delivery to the CNS
Devices that directly treat CNS pathology
Pharmacologic approaches to overcoming the BBB
Devices for delivery of therapeutics to the CNS
Nanoparticles and liposomes for drug delivery
Gene therapy for CNS pathology
Clinical trials using convection enhanced delivery
Regulatory considerations for delivery of therapeutics directly into the CNS
Mathematical and computational modeling of transport in the CNS
Year(s) Of Engagement Activity 2017
 
Description Society for Neuro-Oncology Meeting - New York 15th/16th June 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Society for Neuro-Oncology Meeting - New York 15th/16th June
Year(s) Of Engagement Activity 2017
 
Description World Society of Stereotactic and Functional Neurosurgery (2013) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact • World Society of Stereotactic and Functional Neurosurgery (WSSFN) SSG
o Speaker
o held in Tokyo, Japan
o from May 27- 30, 2013.


I gave a talk with regard to our experiences with techniques of direct intracranial drug delivery.
Year(s) Of Engagement Activity 2013