Scholarly article on topic 'Chronic, intermittent convection-enhanced delivery devices'

Chronic, intermittent convection-enhanced delivery devices Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Owen Lewis, Max Woolley, David Johnson, Anne Rosser, Neil U. Barua, et al.

Abstract Background Intraparenchymal convection-enhanced delivery (CED) of therapeutics directly into the brain has long been endorsed as a medium through which meaningful concentrations of drug can be administered to patients, bypassing the blood brain barrier. The translation of the technology to clinic has been hindered by poor distribution not previously observed in smaller pre-clinical models. In part this was due to the larger volumes of target structures found in humans but principally the poor outcome was linked to reflux (backflow) of infusate proximally along the catheter track. Over the past 10 years, improvements have been made to the technology in the field which has led to a small number of commercially available devices containing reflux inhibiting features. New method While these devices are currently suitable for acute or short term use, several indications would benefit from longer term repeated, intermittent administration of therapeutics (Parkinson's, Alzheimer's, Amyotrophic lateral sclerosis, Brain tumours such as Glioblastoma Multiforme (GBM) and Diffuse intrinsic Pontine Glioma (DIPG), etc.). Results Despite the need for a chronically accessible platform for such indications, limited experience exists in this part of the field. Comparison with existing method(s) At the time of writing no commercially available clinical platform, indicated for chronic, intermittent or continuous delivery to the brain exists. Conclusions Here we review the improvements that have been made to CED devices over recent years and current state of the art for chronic infusion systems.

Academic research paper on topic "Chronic, intermittent convection-enhanced delivery devices"

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journal of Neuroscience Methods xxx (2015) xxx-xxx

ELSEVIER

Contents lists available at ScienceDirect

Journal of Neuroscience Methods

journal homepage www.elsevier.com/locate/jneumeth

Chronic, intermittent convection-enhanced delivery devices

Owen Lewisa b c'*, MaxWoolleyb, David Johnsonb, Anne Rosserc, Neil U. Baruab, Q2

Alison S. Bienemannb, Steven S. Gillb, Sam Evansa

a School of Medical Engineering, Queen's Building, Cardiff University, The Parade, Cardiff, CF24 3AA, UK

b Functional Neurosurgery Research Group, University of Bristol, School of Clinical Sciences, Southmead Hospital, Learning & Research Building, UK c Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK

HIGHLIGHTS

State of the art review of catheter designs for convection-enhanced delivery.

Analysis of the design features, materials and methods of use which could be applied to chronic intermittent drug delivery systems and clinical trials to minimise risk of trial failure and opportunities to optimise intraparenchymal distributions.

ARTICLE INFO

ABSTRACT

Article history:

Received 24 August 2015

Received in revised form 28 October 2015

Accepted 6 November 2015

Available online xxx

Keywords:

Convection-enhanced delivery (CED)

Optimisation

Chronic

Intermittent

Catheter

Background: Intraparenchymal convection-enhanced delivery (CED) of therapeutics directly into the brain has long been endorsed as a medium through which meaningful concentrations of drug can be administered to patients, bypassing the blood brain barrier. The translation of the technology to clinic has been hindered by poor distribution not previously observed in smaller pre-clinical models. In part this was due to the larger volumes of target structures found in humans but principally the poor outcome was linked to reflux (backflow) of infusate proximally along the catheter track. Over the past 10 years, improvements have been made to the technology in the field which has led to a small number of commercially available devices containing reflux inhibiting features.

New method: While these devices are currently suitable for acute or short term use, several indications would benefit from longer term repeated, intermittent administration of therapeutics (Parkinson's, Alzheimer's, Amyotrophic lateral sclerosis, Brain tumours such as Glioblastoma Multiforme (GBM) and Diffuse intrinsic Pontine Glioma (DIPG), etc.).

Results: Despite the need for a chronically accessible platform for such indications, limited experience exists in this part of the field.

Comparison with existing method(s): At the time of writing no commercially available clinical platform, indicated for chronic, intermittent or continuous delivery to the brain exists.

Conclusions: Here we review the improvements that have been made to CED devices over recent years and current state of the art for chronic infusion systems.

© 2015 Published by Elsevier B.V.

Contents

1. Introduction ............................................................................................................................................. 00

2. Intracranial CED devices ................................................................................................................................ 00

2.1. End port cannula (EPC)..........................................................................................................................00

2.2. Shunts and peritoneal catheters used for CED (including multi-port catheters (MPC)) ....................................................... 00

2.3. Micro porous tipped cannula (PTC).............................................................................................................00

2.4. Balloon tipped catheters (BTC)..................................................................................................................00

2.5. Stepped profile cannula (SPC) assemblies ...................................................................................................... 00

* Corresponding author. Tel.: +44 1453524634. E-mail addresses: owen.lewis@renishaw.com, lewisto1@cardiff.ac.uk (O. Lewis).

http://dx.doi.org/10.1016/jjneumeth.2015.11.008 0165-0270/© 2015 Published by Elsevier B.V.

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3. A systems based approach..............................................................................................................................00

4. Discussion...............................................................................................................................................00

5. Conclusions.............................................................................................................................................00

Disclosures..............................................................................................................................................00

Acknowledgments......................................................................................................................................00

References..............................................................................................................................................00

1. Introduction

With global population and predicted lifespan increasing, the prevalence of neurological disease is set to rise. At present over 4.6 million patients have been identified with Parkinson disease (PD) in the top 10 populated countries of the west (with an undefined global population) while there are in excess of 20 million patients globally who suffer with Alzheimer disease (Dorsey et al., 2007; Kowal et al., 2013). Forecast burden models show predicted volumes of PD cases doubling within 15-25 years, while Alzheimer disease is predicted to triple (81.1 million) by 2040 (Lopez, 2011; WHO, 2006). This will place a very high demand on healthcare resources all over the world.

As has previously been reported, oral and intravascular medication are ineffective against these types of pathologies given that <1% of systemically administered drugs reach the brain (Stockwell et al., 2013). A series of tight junctions in the endothelial layer of the vascular system provides a highly effective filtration system that prevents the transport of therapeutic molecules to the tissues and fluids of the brain. This filtration system is called the Blood Brain Barrier (BBB) (Bauer et al., 2014).

Bypassing the BBB and delivering therapeutics directly to the parenchyma, offers the user the ability to introduce therapeutics locally, at doses and concentrations that would otherwise have to be delivered at toxic levels systemically. Bolus injection and the reliance on natural diffusion from the point of delivery, is not a valid administration paradigm as the spread of the therapeutic is limited to a few millimetres from the cannula. Delivery of infusate via a pressure driven regime amplifies the distances permeated by macromolecules and produces a more continuous concentration distribution (Bobo et al., 1994; Morrison et al., 1994). This technique, convection-enhanced delivery (CED), replicates the bulk flow of fluid through the interstitial spaces observed in natural processes, such as vasogenic oedema, by increasing the pressure local to a point source. Therapeutic is driven homogenously into tissues beyond the infusion boundary that would be achieved by diffusion alone (Fig. 1). Intuitively, smaller molecules were associated with larger dispersions than bigger molecules however receptor binding, charge and other molecular properties also impact on the distribution of an infusate (Saito et al., 2006).

Despite positive results pre-clinically (Gash et al., 1996) and in phase I clinician led studies (Gill et al., 2003; Patel et al., 2013; Slevin et al., 2005) clinical translation of CED has been hampered by high profile failed studies (Kunwar et al., 2010; Lang et al., 2006). Retrospective investigations have found that overly ambitious study design, catheter target accuracy and predictability of distribution were major factors failing to achieve successful outcomes (Mueller et al., 2011; Sampson et al., 2010).

Recent improvements, notably to the delivery platform, has reinvigorated the application of clinical CED with eight active studies registered (ClinicalTrials.gov, 2015). More studies that do not require registration may also be active.

A small number of devices have been commercialised which display good acute performance when used with the principles of CED (Brady et al., 2014; Richardson et al., 2011). Progress in this field has therefore focused on acute or short term infusions. These devices are suited to the delivery of small volume payloads for the delivery

Cannula/ Catheter

High concentration

—----------region associated

i with CED

Limited lateral distribution ^associated with bolus injection

Distance from catheter

Fig. 1. Graphic depiction comparing the distribution associated with convection-enhanced delivery (CED) and bolus injection (reproduced and modified from Lam et al. (2011)). Note that the region of high concentration has spread laterally a much larger distance from the catheterthan simply injecting a bolus which is the signature ofCED.

of viral vectors and stem cells, but little exists in the experience of chronic CED applications.

Chronic, intermittent delivery could be useful to treat a range of neurological diseases such as Alzheimer's, Parkinson's (Gill et al., 2003), Gaucher disease (Lonser et al., 2005) among others where repeated infusions could maintain elevated levels of therapeutic within a target tissue, where it is quickly cleared or metabolised (e.g., chemotherapy). While the application of chronic CED may be useful in the treatment of brain tumours such as Glioblas-toma Multiforme (GBM) and Diffuse Intrinsic Pontine Glioma (DIPG) tumours, targeting strategies will be key to place long term catheters in areas of likely recurrence. While direct targeting of a tumour will deplete its core of dividing cells, the resulting necrotic core may act as a sump for further therapeutic delivered, preventing convection into the surrounding tissues. Catheters will need to be placed around the periphery of a tumour in areas of likely recurrence.

Broadening the knowledge of this niche has been hindered in part by the lack of commercially available chronic CED systems to undertake clinical research. Given the predicted volume ofdemand for intraparenchymal delivery options, including chronic administration systems, a new appreciation of the field must be generated. Novel, chronic systems will provide clinicians 'enabling technology' to treat patients and provide the pharmaceutical industry a new platform to develop therapeutics.

As highlighted in the following review, a large range of catheter profiles have been reported following use in CED infusions. Debin-ski and Tatter previously highlighted five categories of catheter design category (Fig. 2); End Port Cannula (EPC), Stepped Profiles Catheters (SPC), Multi-Port Catheters (MPC), Porous tipped catheters (PTC) and Balloon Tipped Catheters (BTC) (Debinski and Tatter, 2009). Designs are not limited to these categories however and numerous variations and overlaps exist.

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Fig. 2. Device design groups used in CED studies (left to right); End Port Cannula, Multi-Port Cannula, Porous Tipped Catheters, Balloon Tipped Catheters and Stepped Profile Catheters—image reproduced and modified from Debinski and Tatter(2009).

Here we review and consolidate information on catheter design, experience and materials which have been published when performing CED infusions in pre-clinical and clinical studies over the past 20 years. This review of the state of the art will guide the design and optimisation of new chronic intraparenchymal catheters and their use.

2. Intracranial CED devices

2.1. End port cannula (EPC)

Much of the earliest work which categorised the basic knowledge of CED was performed with EPC. While EPC are defined as having a singular external profile, no restriction is made to the material, devices can be rigid (e.g., fused silica, PEEK or steel hypotube) or flexible (e.g., polyurethane, silicone).

Bobo et al. (1994) first defined the Vd/Vj ratio, a multiplication ratio used to describe the proportional increase in volume distributed in the brain (Vd) from the volume infused (Vj). Bobo observed that the Vd/V ratio was not constant for all infusions. Smaller molecules displayed larger distributions (Bobo et al., 1994). Later studies highlighted that the ratio was also linked to the tissue type, as the interstitial fraction is lower in grey matter than white matter (Lieberman et al., 1995). Larger volumes and faster infusion rates developed to infuse clinically relevant volumes in an acceptable timeframe. Increases in flow rates were however linked to increases in the amount of reflux (leakback/backflow) along the catheter track (Chen et al., 1999). Reflux is detrimental to CED as the loss of fluid around the point of distribution drops the local pressure, limiting further distribution. Leakages into unintended regions can lead to unwanted side effects (Nutt et al., 2003; Tanner et al., 2007). Investigation of infusion parameters affecting distribution identified that increases in cannula diameter strongly correlated to increases in the volume and distance of reflux (Chen et al., 1999; Fig. 3) which was also predicted mathematically (Morrison et al., 1999). Increasing the concentration of the infusate or delaying the start of an infusion (tissue-to-catheter sealing time) were discounted experimentally as having little to no effect on reflux. However, it was later shown that increases in tissue trauma (common with larger bore devices) positively correlated to volume and extent of reflux (White et al., 2011). The sealing times described by Chen would not have been long enough for healing mechanisms to reduce oedema associated with local trauma allowing the tissue to seal around the device.

Fig. 3. Increases in flow rate have been shown empirically to generate increases in reflux along the catheter track—graph reproduced and modified from Chen et al.

(1999).

2.2. Shunts and peritoneal catheters used for CED (including multi-port catheters (MPC))

Hydrocephalus shunts, designed for long term implantation in the brain are routinely used to deliver and aspirate liquids to and from the ventricles in the brain. They are made from flexible materials such as silicones or polyurethanes. Shunts typically come with an end port, fish mouth or multiport design and usually have a large bore (>1 mm) to aid the rapid clearance of excess cerebrospinal fluid (CSF). Shunts however may not be optimal for CED as they lack functional features (i.e., small diameters, reflux inhibiting profiles, etc.; discussed later) which are critical to effectively distribute infusates into the interstitial fluids of the brain through pressure driven means.

Large calibre, flexible end port style ventricular catheters (2-3 mm outer diameter) that have been implanted in clinical trials to treat glioma have failed to distribute effectively and have been linked to poor distributions (Kunwar et al., 2010; Tanner et al., 2007). Cases treating Diffuse Intrinsic Pontine Glioma (DIPG), assumed spherical distribution but required a low flow rate, ~1 |il/min to delivery (~6ml in 100 h), to minimise the risk of reflux. As no diagnostic tracer was used to confirm the distribution (as acknowledged by the author) it is not possible to evaluate the infusion effectively, however, T2 weighted MRI scans indicated some elevated signal around the catheter tip (Anderson et al., 2013).

In other phase I clinical trials, multi-port catheters were implanted into the striatum of patients with promising results (Slevin et al., 2005). It was suggested that the increased number of holes may have aided delivery of therapeutics to the parenchy-mal tissues but as no post infusion imaging was performed on the distribution of these infusions it is impossible to fully qualify this assertion.

Subsequent investigations of MPC for CED in gel showed that they performed poorly (Raghavan et al., 2006; Salvatore et al., 2006) with preferential flow occurring from the proximal holes.

Investigations of multiport hydrocephalus shunts (Lin et al., 2003) demonstrated that of the available eight holes along the device, 80% of the flow escaped from the most proximal three holes (Fig. 4). This was proven empirically and then supported through a Computational model.

Preferential flow seen in hydrocephalus devices might help explain the patterns of distribution seen in CED studies using these devices in the opposite flow direction.

2.3. Micro porous tipped cannula (PTC)

PTC are similar to MPC in that they have a number of holes along their outer wall but PTC have a much larger number of

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MPC flow profile

1— n_ f~L f~L

□ Modified

12345678 Hole # (Left-Distal/ Right-Proximal)

Fig. 4. Graphical representation of uneven flow distribution within multiport hydrocephalus catheters (black) and a more even flow which could be achieved through modifications to the hole profiles and arrangement (white). The distal end is shown on the left of the graph—image reproduced and modified from Lin et al. (2003).

220 much smaller holes (<0.45 |im diameter). These holes make up the

221 porous, ceramic walls in the tips of these devices. During an infu-

222 sion, each pore experiences a very small volumetric flow which

223 will drop the pressure within the core of the device by an equally

224 small amount. By maintaining a high internal pressure more dis-

225 tal pores also experience a modest flow which contributes to the

226 overall distribution along the length of the porous tip (Fig. 5).

227 When compared to EPC the PTC was shown to increase the dis-

228 tribution of infusate into the surrounding gel substrate and murine

229 brain tissue (Oh et al., 2007). A later study found that PTC cannula

230 produced a comparable infusion profile to 3 mm step profile can-

231 nula in vivo (Brady et al., 2013). PTC are being commercialised for

232 drug delivery by Twin Star Medical.

233 2.4. Balloon tipped catheters (BTC)

234 While not commonly used in CED trials, a small number of stud-

235 ies have shown that BTC may have use in treating oncology subjects

236 who have undergone resection of their tumour mass. As the penum-

237 bra of a resection cavity is most at risk of metastasis, it has been

238 argued that infusions targeting dividing cells should be admin-

239 istered preferentially into these areas. Intra-ventricular infusions

240 have shown little diffusion of infusate beyond the ependymal layer

241 of the ventricles (Nutt et al., 2003) while catheters placed too close

242 to a resection cavity have been linked to losses into these CSF

243 spaces, dramatically stagnating further distribution into surround-

244 ing tissues (Sampson et al., 2011).

245 A team at Emory University performed resections in canine sub-

246 jects with the aim of investigating whether CED could be effectively

247 used to distribute infusate into a tumour penumbra by first filling

Fig. 5. Microporous tipped cannula (a) illustration of even flow possible over elongated portions of the device (note blocked tip), (b) radial view of the cannula wall showing tortuous pathway for infusate through the porous wall—images reproduced from Oh et al. (2007).

the resection cavity with a balloon (Olson et al., 2008). The study infused continuously for 4 days at a rate of 83 |l/h and stated that in 2 of 3 cases 97-99% of the brain achieved coverage. The images of coverage (Fig. 6), however, do not appear to display the

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252 homogenous distribution profile associated with CED. The large

253 coverage may be attributed to the large concentration of the MRI

254 visible tracer—75% saline/25% Gd-DTPA (Magnevist, Berlex; Olson

255 et al., 2008) and prolonged period of infusion, with gadolinium

256 being carried along with natural parenchymal CSF turnover. Further

257 work is required to expand the knowledge for this application.

258 2.5. Stepped profile cannula (SPC) assemblies

259 Several designs of SPC have been used to perform CED infusions

260 in clinical and pre-clinical studies. Stepped profiles can be produced

261 through the assembly of tubes at the time of implantation or within

262 a monolithic assembly that is implanted as a single unit, although it

263 can be argued that the later exhibits much less traumatic delivery

264 characteristics for acute delivery.

265 Monolithic stepped profiles were pioneered by a team at the

266 University of California, San Francisco (UCSF) showing that where

267 end port cannula alone would have refluxed, the addition of

268 stepped features would inhibit the progression of backflow (Krauze

269 et al., 2005; Sanftner et al., 2005; Fig. 7).

270 The distribution of the stepped profile was evaluated first in

271 agarose gel containers and later histologically following infusions

272 in the rat and primate model. Agarose gel is a standard phan-

273 tom material for brain tissue which has been validated against

274 the porcine brain model (Chen et al., 2004). A monolithic SPC is

275 being commercialised by MRI interventions Inc. which contains a

276 ceramic, fused silica liner and a polymer sheath.

277 Research conducted at Cornell University utilised silicon indus-

278 try technology to manufacture printed cannula tips containing dual

279 lumen. These can be independently coupled to proximal tubing

280 away from a delivery site enabling the delivery of a multitude of

281 infusates in addition to the integration of sensor technology. This

282 could be used during delivery to monitor the local environment or

283 to actively monitor the infusate itself (flow rate, temperature, air in

284 line, etc.; Olbricht et al., 2010). The tip design is being incorporated

285 into a stepped profile cannula and commercialised by Alcyone Inc.

286 Investigations using the dual channel tip were conducted in the

287 porcine model at varying flow rates with a number of infusates.

288 When combined with a stepped profile design comparable

289 distributions to other SPC were achieved. Infusion rates as high

290 as 20 |il/min were published for white (internal capsule) and grey

291 (thalamus, putamen) matter targets but no investigation of tissue

292 damage was conducted (Brady et al., 2014). Earlier studies noted

tissue damage at infusion rates in excess of 10 |il/min when deliv- 293

ered from a cannula with a 102 |im diameter bore. The authors 294

speculated that the tissue damage may be attributed to the delivery 295

of excessive volume however subsequent studies have successfully 296

infused larger volumes (Chittiboina et al., 2014) discounting the 297

theory that volume alone is the cause of the observed tissue dam- 298

age. It is therefore possible that the tissue damage found by the 299

UCSF team may be linked to the fluid velocity at the tip of the 300

catheter. At 10 |l/min, a cannula with a 102 |im internal diame- 301

ter would eject a fluid stream at 5.1 mm/s. Evaluating the smaller 302

cannula outlet produced by the micro-fabricated dual channel tips 303

(30 x 53 |im2), a comparable flow rate may have produced a fluid 304

jet travelling at over 10 times this rate. It is therefore essential that 305

new cannula and catheter designs are tested not only for perfor- 306

mance with diagnostic imaging but the infusion regimes must be 307

validated at a cellular level to provide future users a set of safe oper- 308

ational parameters. Further investigation of this and other designs 309

is therefore warranted. 310

Prior to the release of commercial alternatives, other groups 311

treating DIPG clinically have pre-clinically investigated the use of 312

FS components from Plastics one, a supplier of pre-clinical infusion 313

systems, before implanting a similar device in humans. A large bore 314

guide tube (16-18 Gauge) is implanted into the brain stereotacti- 315

cally and is bonded into a burr hole formed in the cranium, with 316

the distal tip 15-35 mm short of the target. A primed silica catheter 317

is then inserted to depth in the guide tube, with the tip located in 318

the brainstem (Lonser et al., 2002, 2007a,b). 319

Monolithic SPC usually combine steel or ceramic tubing with 320

fused silica (FS) liners. This rigid construction is advantageous for 321

acute infusions as devices can be implanted with a stereotactic 322

guide system which helps minimise macro-motion during inser- 323

tion and infusion which is critical to reducing reflux (Chen et al., 324

2004). Long term implantation of these monolithic assemblies is 325

not feasible due to the rigidity of the cannula. The relative move- 326

ment between the brain and the device will promote reflux but may 327

also accelerate natural healing processes. We postulate that as the 328

brain encases the device in a sheath of glial tissue the permeability 329

around the cannula will drop which may further increase reflux. 330

A modified hybrid of the monolithic SPC (Fig. 7) made from flex- 331

ible tubing and a rigid, FS tip was investigated by the same team at 332

UCSF, Medgenesis Therapeutics and Brainlab AG. This enabled the 333

device to be implanted in a rigid state (to aid stereotactic delivery), 334

before a delivery rod was removed leaving the flexible, indwelling 335

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Fig. 8. Decrease in the intensity of a gadolinium tracer in the brainstem following the end of an infusion (A) immediately after completion of the infusion, (B) after 1 h, (C) after 3 h. Note the initial increase in the distribution due to diffusion and clearance processes but the large drop by 3 h post infusion (39% of the Vd at infusion end)—images reproduced and modified from Lonser et al. (2007a).

device (with rigid tip) in situ. The flexible tubing outside the skull could then be routed beneath the skin to a distal exit point. Evidence of acute but not chronic intermittent infusions, in addition to images of the device were published (Rosenbluth et al., 2011).

Similar, stepped catheter designs were fabricated in Medtronic sponsored studies. Needle tip catheters were used in a 10 day study in the porcine model, coupled to an implantable pump (Kim et al., 2014) and later a 28 day study in adult primates (Fan et al., 2015). Following a 3 or 7 day infusion (flow rate; 0.3 |il/min) of a Gd-DTPA solution into the brain, distribution volumes of 1.544 ml ± 0.420 ml (Vd/V = 1.2) were recorded in the pig and 1.936 ±0.660 ml (Vd/V = 1.68) were recorded in the primate. The low distribution volumes may be accounted for by a high clearance rate of Gd-DTPA seen in other studies (Lonser et al., 2007a; Fig. 8). Acute infusions in the primates showed much higher Vd/V ratios (5.56 ±1.6) indicating clearance may be a major factor in low flow, continuous infusion.

In order to cover the larger human putamen (3.98 ± 0.15 ml; Yin et al., 2009) using this system it may be necessary to implant multiple catheters with each attached to a pump. Alternatively, higher coverage ratios might be achieved by running the pump at a higher rate for a short period of time before natural clearance removes the infusate from the local area. Continuous infusions were shown to achieve larger overall infusions. A recent study of prolonged CED in the rat brainstem (Ho et al., 2015) produced no neurological behavioural changes or signs of local toxicity. The relatively short period of the study (10 days) may not have provided sufficient time for the onset of local toxicity due to point source accumulation identified in other studies (Barua et al., 2013b).

Flexible guide tube and catheter assemblies, suitable for long term implantation, were manufactured specifically for a phase I investigational study of Glial cell-line Derived Neurotrophic Factor (GDNF) at Frenchay hospital, Bristol, UK (Gill et al., 2003). Sub 1 mm diameter catheters and guide tubes were used to minimise the risk of reflux which had been shown to occur in larger diameter cannula (Chen et al., 1999). The catheter was manufactured in CarbothaneTM, an aliphatic polyurethane which was later shown to be critical in achieving low blockage rates (Bienemann et al., 2012). Despite promising clinical outcomes in a small number of cases, it was not possible to measure infusion performance of this system as MRI tracers such as gadolinium (Gd-DTPA) were not routinely used.

Fig. 9. Assembled catheter design with a reflux inhibiting feature: a recessed step—images reproduced and modified from Gill et al. (2013).

Successful intermittent infusions performed over 163 days in the porcine model were demonstrated by the University of Bristol, utilising a similar system to that described by Gill in 2003. Novel infusion regimes were used to deliver intermittently which differed from previous, longer term studies in which fluids were supplied continuously from an implanted reservoir pump (Bienemann et al.,

2012). The flexible guide tube assembly was further developed with the incorporation of a third cannula. Instead of a dual step design the central cannula is cut shorter than the outer tube, producing a recessed design (Fig. 9).

We have identified that contrary to the initial description of CED as a point source event (Bobo et al., 1994), infusions naturally involve a degree of reflux which can be incorporated into the infusion distribution model (Woolley et al., 2013). Immediately following the start of an infusion, fluid passes into the interstitial spaces of the surrounding tissue as expected from the standard model. As the pressure continues to build however the contact forces between the outer wall of the catheter and the tissue surrounding it will reach a state of equilibrium. At this point fluid will pass into this space, passing up the outside of the catheter as reflux. As fluid escapes from the tip area the local pressure drops the contact forces high up the catheter track remain high which combined, stem the flow of fluid.

By embracing and this inevitable reflux, we have demonstrated it is possible to exert a degree of control over it. We have previously published evidence on the indwelling performance of the recessed step catheter (Gill et al., 2013) over a month in the porcine model and subsequently within clinical glioblastoma cases (Barua et al., 2013a, 2014). While monolithic SPC utilise progressively larger diameters to inhibit and retard this flow acutely, no chronic infusion data is available therefore their efficacy cannot be stated. A chronic, pre-clinical infusion system and a similar chronic, clinical platform are being commercialised by Renishaw PLC.

A novel aspect of the assembled guide tube platform is the ability to modify the length of the step between the smallest diameter tube (catheter) and the outer guide tube specific to each target site. Together with the recessed step feature, it has been demonstrated that increasing the protruding step length has the effect of minimising the volume of reflux which travels beyond the flow inhibiting step feature, achieving a controlled form of reflux (Woolley et al.,

2013).

We have identified, and will subsequently present data (Lewis, 2015), that it is possible to manipulate infusion morphology through modifications to the step length and the infusion regime of a recessed step catheter. The ability to modify infusion parameters permits non-surgically invasive optimisation of infusion distributions following implantation and potentially longer term.

For chronically implanted devices, attributes such as a 90° bend in the tube at the skull surface, and access via a distal port, facilitate real time monitoring to make informed decisions on the progress of the infusion.

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429 A novel accessory described by a team at the University of Wis- particular therapeutics, such as; molecular size, weight, charge, 470

430 consin creates a 'valve tip' and prevents blockage by occluding tissue affinity together with receptor binding, deactivation and 471

431 the inner bore of the cannula with a solid rod during insertion. potency levels to material and geometry used in the design of the 472

432 Following insertion the rod is retracted a short distance (~3 to implantable device. 473

433 5 mm) within the catheter where the inner bore opens slightly Natural variations in the population as well as a changing inter- 474

434 leaving room for fluid to pass around the rod (Sillay et al., 2012). nal environment over time due to healing processes present further 475

435 This design has the additional benefit of reducing the dead volume complicating factors which demand individual attention and will 476

436 within implanted systems but will increase the pressure required require ongoing evaluation to optimise the infusion regimes to 477

437 to infuse. Comparisons to monolithic stepped cannula designs and ensure the patient receives treatment where it is required. 478

438 also microporous tipped cannula showed that the 'valve tip' design

439 produced comparable infusion profiles but no marked improve-

440 ment in distribution (Brady et al., 2013; Sillay et al., 2012). This 4. Discussion 479

441 design would therefore only offer improved robustness and possi-

442 bly reduced tissue trauma on entry. Following years of basic research which characterised the per- 480

formance issues associated with CED systems, there is now a 481

443 3 A systems based approach growing community which actively use the principles of CED in 482

pre-clinical and clinical investigations of new and existing drugs. 483

444 While this review has focused on catheter design for chronic Despite the immaturity of the knowledge surrounding suc- 484

445 intraparenchymal delivery, previous experience from clinical trials cessful implementation of CED systems and the ability to achieve 485

446 indicates that dealing with problem areas in isolation is the root acceptable coverage of target structures, CED continues to be prac- 486

447 cause of failures to tackle the clinical translation of CED. ticed within a smaU number of research centres who accept the 487

448 Novel delivery platforms for chronic infusions should there- current limitations, enabling the implantation of infusion devices 488

449 fore be founded on the successes pioneered in the acute setting based on empirical, historic knowledge and experience of each 489

450 while incorporating lessons from previous, failed trials to con- device s pri°r performance. 490

451 sider new approaches. While a detailed review of other aspects of A limited number of acute devices have received market 491

452 CED is beyond the scope of this review, here we acknowledge the approval and fewer stiH have received authorisation for marketi- 492

453 inter-relationship between the catheter design and other variables. sation as CED devices, but no commercially available system is 493

454 Chronic, repeated delivery is a complex problem with a number of currently indicated for chronic intraparenchymal delivery. 494

455 interdependent elements that require consideration if optimised, Drug device combination programmes developing pharmaceut- 495

456 reliable and repeatable intraparenchymal drug delivery is to be icals and improving catheter designs are likely to benefit from 496

457 achieved (Woolley et al 2013) development within a systematic, lab to clinic process where first 497

458 This multi factorial approach to successful infusions, depicted principles and empirical evidence combine to optimise the delivery. 498

459 as the pinnacle of the CED pyramid (Fig. 10), relies on expertise and Translation of device design should start with distribution charac- 499

460 knowledge across several disciplines. Here it is believed that opti- terisation in an isotropic, homogenous substrate such as agarose 500

461 mal CED can be attained if based on a solid foundation of effective gel to baseline performance.Distribution properties should then be 501

462 stereotaxy, sophisticated surgical planning software, ridged stereo- confirmed pre-clinically within in vivo models before finally being 502

463 tactic delivery instruments and appropriate, responsive infusion translated to clinical indications. 503

464 pumps While only an indicator of infusion morphology, we have found, 504

464 It seems likely that only once a solid platform is achieved andwillsubsequentlybepublishing,thatagarosegelinfusionsoffer 505

466 can reflux resistant chronic drug delivery systems be implanted baseline infusion morphology data which is specific to each device. 506

467 with the required accuracy to ensure that critical catheter features Reflux inhibiting features can be trialled and gain a degree of sup- 507

468 are positioned within target structures. The CED pyramid also porting empirical evidence before it is trialled in the complex in 508

469 illustrates the need to consider contributing factors that affect vivo environment. Users must appreciate that gel data resents an 509

excellent starting point which can inform clinical decisions but 510

this is only a starting point and knowledge of the infusion dis- 511

tribution properties of the local structures (and more preferably, 512

prior clinical experience) should be incorporated into the planning 513

effective and implementation process. Published evidence of safe, achiev- 514

infusions able distributions in the in vivo pre-clinical model should also form 515

^ the basis of a CED practitioner's planning arsenal, specifically whilst 516

•-O implantable this technique is being adopted and experience gained. 517

brain DEV'CE drug ■■fi In order to enable optimisation of infusion systems follow- 518

structure <5^. ing implantation, it is beneficial for flexibility to be built in to 519

S* ^<5/ study or treatment protocols. It is now obvious that CED infusions 520

jl> molecule infusate <S> must be visualised following the implantation of chronic infu- 521

sion systems to confirm target acquisition and characterise the 522

distribution achieved. Where poor target structure coverage or 523

other undesirable distributions are observed, clinicians must be 524

given the knowledge of how best to intervene and optimise the 525

software expertise sets distribution. It is unacceptable to permit treatments or trials to 526

fail where the technology exists, and can be easily implemented, 527

DEm/ERY to modify the input infusion regimes and improve outcomes for 528

patients. Such a controllable infusion system will maximise clinical 529

benefits and reduce the risk of adverse events while accelerating 530

Fig. 10. Pyramid of effective drug delivery to the brain—image reproduced and the development of new drugs to clinic. Pre-clinical correlation 531

modified from Woolley et al. (2013). mapping of a pharmaceutical agent to imaging tracers should 532

■BH^^H ARTICLE IN PRESS

O. Lewis et al. / Journal of Neuroscience Methods xxx (2015) xxx-xxx

533 precede clinical use to ensure representative diagnostic imaging

534 interpretations.

535 For chronic infusions, periodic mapping of the distribution,

536 using diagnostic imaging tracers, will help characterise ongoing

537 distribution of therapeutics within target tissues and permit inter-

538 vention to optimise coverage.

539 Following the initial description of CED which used simple

540 cannula, development of infusion parameters (flow rate, ramping

541 regimes, etc.) have preceded device development. Numerous infu-

542 sion cannula and catheter systems have since been trialled for CED

543 with varying degrees of success. Published distribution data indi-

544 cates that each device performs differently and infusion parameters

545 should be developed for each device to optimise distributions. All

546 systems will benefit from further investigation and clinical use to

547 generate a better understanding of their performance attributes.

548 A small number of physical attributes appear critical across all

549 designs which can be translated to that of a chronically implanted

550 catheter system.

551 Larger diameters are linked to increased distance of undesirable

552 reflux along the catheter track. Large diameter tubing is therefore

553 undesirable for intraparenchymal delivery. Increases in infusion

554 rates raise the local pressure around the infusion site and also

555 increases the extent of reflux if the pressure surpasses that required

556 to achieve bulk flow of the interstitial fluid. If reflux is observed then

557 further distribution is limited as the additional infusate follows the

558 path of least resistance around the catheter. Actively dropping an

559 infusion rate may decrease the pressure local to the site of reflux

560 and halt further progression.

561 From this review and from our own work, we have found that

562 a reflux inhibiting feature is required to halt backflow along the

563 catheter entry track. Simultaneously this maximises local inter-

564 stitial pressure and achieves bulk flow of the therapeutic into the

565 tissue volume.

566 For prolonged chronic indications it is essential that the catheter

567 systems are made from a flexible material which can move with the

568 brain during every day activities. All devices must be placed accu-

569 rately without lateral macro motion as this can increase trauma

570 and have a detrimental effect on the distribution.

571 In addition to physical features, certain practical and transfer-

572 able attributes are essential for CED devices to facilitate this novel

573 treatment regime.

574 If we accept that the local environment surrounding each

575 catheter site is unique and each patient specific, then it is unlikely

576 that a standard infusion regime will produce comparable distri-

577 butions between patients. Catheter specific optimisation may be

578 required to achieve acceptable coverage of the target structure.

579 Therefore catheter designs need to be flexible so that specific fea-

580 tures that inhibit reflux can be optimally placed in the intended

581 target structure.

582 Devices must be compatible with imaging modalities such as

583 MRI (or nuclear imaging in the cases of radio-labelled markers) to

584 enable real time visualisation of distributions to verify acceptable

585 coverage or intervene and implement a modified infusion regime

586 to optimise the distribution. Until a standard model of repeatable

587 delivery is achieved patient specific infusion regimes provide a

588 practical method of providing patients with optimal coverage of

589 targeted tissues (Healy and Vogelbaum, 2015). As an emerging field,

590 CED will require specialist clinical infusion pumps and software

591 that are capable of running at low infusion rates (0.1-10 |il/min).

592 Pump or pump software should have the functionality to house

593 patient specific infusion regimes which can be categorised at test

594 infusion milestones (e.g., first infusion).

595 There are a range of pre-clinical and clinical options for acces-

596 sing intracranial catheter systems. Active, implantable osmotic

597 pumps (Alzet®) are routinely used to continuously deliver

598 infusate pre-clinically. More recently Alzet® have manufactured a

programmable, micro infusion pump containing a 900 |il reservoir 599

which can be programmed to run intermittently using an on board 600

micro-processor (iPrecio®) and a radial peristaltic pump.This micro 601

pump has a maximum flow rate of 0.5 |l/min. While not indicated 602

for it, the low peak rate would be of limited clinic use to achieve CED. 603

Passive subcutaneous access ports (e.g., PinPorts/Soloports, 604

Instech Solomon, Portacath, Smiths Medical, Porthales, Tricumed 605

Medizintechnik GmbH, etc.) provide a means of periodically acces- 606

sing implanted catheter systems injecting into or cutting down to 607

make the connection immediately prior to an infusion. While sub- 608

cutaneous ports, osmotic and reservoir pumps can be connected to 609

intracranial catheters, chronic infusion systems may benefit from 610

having an externally accessible port to facilitate easy connection 611

and prolonged attachment during infusions (several hours) with 612

minimal implanted hardware (Barua et al., 2013b, 2014). 613

Despite a small number of commercially available reflux resis- 614

tant catheter designs, and some stiff tipped indwelling catheters, 615

no evidence of their chronic efficacy is available. Further work 616

is required to develop knowledge of how to implant, optimise 617

and maintain chronically implanted convection-enhanced delivery 618

infusion systems. 619

5. Conclusions 620

Forecast burden models indicate that the growing and ageing 621

global population will cause a steep rise in the prevalence of neuro- 622

oncology and neurodegenerative disease which will place a high 623

demand on palliative healthcare resources. 624

Convection-enhanced delivery provides a paradigm for phar- 625

maceutical and academic institutions to provide not only acute 626

infusions of gene therapy but also chronic, intermittent infusions of 627

proteins, neurotrophic factors, chemotherapeutics or other quickly 628

metabolised molecules. 629

A small number of dedicated CED devices are starting to enter 630

the marketplace but are targeted at acute, stereotactic delivery. No 631

devices are commercially available which are indicated for chronic, 632

intermittent CED to the brain parenchyma. 633

Targeted chronic catheter and study design should be developed 634

to enable development of novel treatment regimes which can be 635

based upon the principles developed within acute delivery systems. 636

All catheter designs have unique attributes which must be char- 637

acterised to be used effectively. It should not be assumed that 638

infusions parameters can be utilised uniformly across all commer- 639

cially available catheter platforms. 640

Chronic infusion catheter systems will benefit from small diam- 641

eters and the inclusion of reflux inhibiting features. To remain in the 642

brain long term, catheters will need to be made from soft materials 643

but still need to achieve excellent target accuracy which is likely to 644

require a 'systems based approach' which tackles peripheral issues 645

around the design of the catheter to ensure effective delivery. 646

Following implantation, and initial characterisation of the dis- 647

tribution, further periodic test infusions will be required to assess 648

changes to the distribution pattern which may be caused by heal- 649

ing mechanisms and natural changes to the internal environment. 650

In order to do this, device design must facilitate real-time imag- 651

ing, enable alterations to infusion distribution and be minimally 652

invasive whilst maximising the patient's quality of life. 653

Further work is required to generate understanding of infu- 654

sion distributions which can be achieved by utilising chronically 655

implanted CED systems. 656

Disclosures 657

While undertaking the research for this review, O. Lewis, M. 658

Woolley and D. Johnson were employees of Renishaw PLC. 659

I I'M^^^B AIIIIII.E IN PRESS

O. Lewis et al. / Journal of Neuroscience Methods xxx (2015) xxx-xxx 9

S.S. Gill, N.U. Barua and A.S. Bienemann were consultants to Renishaw PLC.

O. Lewis is undertaking a part time PhD at Cardiff University which is funded by Renishaw PLC.

Acknowledgments

Special thanks go to the Functional Neurosurgery Group at Bristol University and Renishaw's Neurological Applications Department for collaborative work towards research work yet unpublished.

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