Biomedical Engineering Reference
In-Depth Information
6.1.3.1 Intracerebral routes
Intracerebral delivery involves delivery of the drug directly into the brain
parenchyma. Drugs can be injected directly via intrathecal catheters, by con-
trolled release matrices, microencapsulated chemicals or recombinant cells.
These strategies are, however, highly invasive and disadvantages such as infec-
tion, catheter obstruction and discomfort for the patient have been reported.
These invasive strategies rely on the diffusion of therapeutic molecules, but
this mechanism is very limited in the cerebral parenchyma. Intraventricular
drug infusion involves placing a catheter into the cerebrospinal fluid of the
ventricles, and relies on drug diffusion from local depot sites to the brain
parenchyma. The major problem with bolus injection is slower movement of
compounds within the brain due to the limited diffusion coefficient. Hence
a large amount of dose is required for an appropriate drug concentration in
the parenchyma. However, diffusion is a poor mode of drug delivery to the
brain, and the limited volume of distribution of therapeutic drugs into the
brain limits the value. Because the cerebrospinal fluid is completely absorbed
into the venous circulation, the infused drug into ventricular spaces is rap-
idly transported to the peripheral blood circulation, with minimal penetra-
tion into the brain parenchyma. A similar approach has been used for the
intraventricular or intracerebral injection of genetically engineered cells that
secrete a specific protein factor, or the injection of biodegradable polymer
that releases the therapeutic substance. The Ommaya reservoir, a catheter
with a pump system, can deliver intermittent bolus injections of antican-
cer drugs directly into the CSF. Similarly vapour pressure activated devices
like the Ommaya® reservoir pump (Vygon Neuro, Norristown, USA)
(a dome-shaped device, with a catheter attached to the underside used to
deliver chemotherapy) containing etoposide, an antitumor agent used for
treating metastatic brain tumor showed 100-fold more effective concentra-
tion. Local and site-specific delivery of chemotherapeutic agents' increases
drug concentration at the tumor target, decreases systemic exposure and
toxicities, and increases the duration of exposure of the tumor to the drug.
Experimental and clinical studies have demonstrated a statistically sig-
nificant increase in survival associated with local therapy for brain tumors
[234]. The intrathecal route involves delivery of neurotherapeutic agents to
the brain by direct administration of drugs through the intrathecal route
into the cisterna magna of the brain. Though it is substantially less invasive
than intraventricular administration, this method fails to result in drug ac-
cumulation in parenchymal structures of the deep brain, which is highly
essential for sustained drug release. The major disadvantage of this route is
the chance of the drug spreading along the distal space of the spinal canal,
which was understood when etoposide administered through this route into
dogs led to ataxia and loss of muscle coordination. The general principle
of convection-enhanced delivery (CED) involves the stereotactically guided
