Michal

alzet is the only manufacturer that I am aware of. At least the only one anyone publishes as having used. To get longer than 6 weeks you can take out the exhausted pump and replace it with a new one. We used to do this before the 6 week pump came along. cheers

john

Hi John,

Thanks a lot for that. We hoped to be able to cover at least 2 months of acclimation without the need to reimplant pumps.  Looks that reimplantation is inevitable.

Cheers,

michal

I think a problem is that as pump duration gets longer then either the pump needs to get much larger to deliver the material at the same rate or the delivery rate needs to decline. A limit then may be the soluability of whatever it is you are pumping in to get a biologically active dose.  Six weeks may be the limit to get a reasonable sized pump for implantation into mouse sized animals, while delivering at a suitable rate. It might be worth contacting Alzet direct to see what they suggest. If you do please post the answer on here as I think lots of people would be interested in the ability to pump in compounds for >6 weeks. 

John

Interesting question and I'd be happy to see a broad discussion on sustained-release techniques.  As John, I'm only aware of Alzet as a manufacturer of osmotic minipumps. Probably, they have this clever idea of sustained delivery patented. 

While their minipumps deliver a steady volume of the loaded solution, the question remains, what's the effective dose of the active substance when it's been in solution kept at 37C (in the mammal) for weeks on end?

The alternatives are solid delivery systems such as cholesterol-based pallets we've used for peptide hormones och silastic tubes for steroids. In both instances, the hormones are slowly dissolving and entering the circulation. There is however near impossible to know the dose being delivered unless you carry out complex pharmacokinetics studies.

Hi John and Björn,

I contacted Alzet and asked the following:

We are planing a long term study in which we would like to continously deliver hormones to mouse-sized mammals. We would like to be able to acclimate them to various conditions during the study. The acclimation will take ~10-12 weeks. Thus, I would like to ask you if you could suggest any solution for a long term delivery which would allow us to deliver the hormones without the need to reimplant animals. From that what I found on your website I understood that your longest lasting pumps work for maximum 6 weeks. Is there any way to overcome this?

And this is the answer I got:

You are correct in stating that our longest lasting pump, model 2006, infuses for a maximum of six weeks. Previous research using ALZET Pumps have had infusion durations for as long as 32 weeks in mice. However, this is only possible with serial reimplantation of pumps. Without the option of reimplantation, the maximum infusion possible in a mammalian species is six weeks. The protocol for subcutaneous serial reimplantation is undemanding, requires only a minor surgical procedure, and is also generally well tolerated in animals.

So, 6-week pumps are the longest-lasting. But here is a paper by Turek et al. (attached) who constructed pumps on their own. I do not think that I will be doing it on my own, but maybe it will be useful for you.

cheers,

michal

The point about compound stability in solution at 37 oC by Bjorn is well made.

As a practical example of this. We did a study previously infusing apelin-13 directly into the brain (Valle et al 2008 J. Neuroendocrinology 20: 79-84). We found a strong initial effect on food intake (days 3 to 7) but the effect then converged on that of controls. Mass spec analysis of the contents of pumps in an in vitro experiment at 37 oC showed that this was probably due to the progressive conversion of apelin-13 to Pyr1-apelin-13, involving removal of a NH2 group and conversion of the terminal glutamine to pyroglutamine. Pyr1-apelin-13 has has a 4 fold lower receptor binding affinity at the APJ receptor probably explaining the waning food intake effect over time....and this was just a 10 day infusion experiment.

Clearly however these issues are going to be compound specific. Before embarking on a big experiment however it would be good to check compound stability in the pump over 6 weeks at 37oC to make sure what you are pumping in at the end is the same as what you are pumping in at the start.

cheers, john 

Hi John. Your example of deactivation of a compound over time is illuminating. I'm sure that your data could easily have been misinterpreted as desensitization if you hadn't checked the integrity of the compound.

I recall a creative approach to using the Alzet minipumps in endocrinological research by the group of Paul Licht when I was at UC Berkeley in the 80's, but I'm not sure if it resulted in publications.

At least some of the pumps can be attached to a catheter, and what they did was to fill a catheter with small volumes of hormonal solution (probably thyroid hormone) separated within the catheter by sections of air. They then made a coil of the catheter and implanted the pump and the coil. Theoretically, at least, this would result in a pulsatile release of hormone from the implant! I thought this was really clever, especially in the light of the fact that pulsitility is often an extremely important feature of hormonal regulation.

One has to recognize that none of the synthetic materials are entirely inert when implanted. At least in part, the necessity to use a new device at six weeks or before has to do with the fact that natural responses of body start creating a barrier in the form of deposited proteins, which interfere with normal diffusion of the contents within the Alzet pump. 

In our hands, Alzet pump was less than linear even for the first four weeks. 

Dear Tausif,

That is a great point. Indeed, whatever you implant gets covered with connective tissue quite fast. I forgot about this issue while thinking about osmotic implants.

Michal

Hi Michal, 

Not sure if you are still interest in longer duration pumps. You can find information here, www.iprecio.com. SMP-200 pump (rats) go for 6 months and you can refill if test article is not stable

Thank you,

michal

You are welcome

Tsung