Routes of Administration at ANOVA IRM
Does MSC secretome cross the
blood–brain barrier?
With intrathecal application the question does not arise: the blood–brain barrier is not crossed, it is bypassed. The preparation is delivered by lumbar puncture directly into the cerebrospinal fluid and is therefore already inside the central nervous system. The question is pertinent for an infusion into a vein, and there the honest answer is: in part, but only to a small extent. How the puncture itself works is described on the page about intrathecal application.
Which barriers lie between blood, cerebrospinal fluid and brain?
Three interfaces are frequently confused, and only two of them are true barriers.
- The blood–brain barrier (BBB) is formed by the endothelium of the cerebral capillaries and its tight junctions. It separates blood from brain tissue and is impermeable to most medicinal products.
- The blood–CSF barrier lies at the epithelium of the choroid plexus and separates blood from cerebrospinal fluid. It is anatomically and functionally distinct from the BBB.[1]
- The CSF–parenchyma interface (pia mater with glia limitans, and the ependyma) is not a barrier in the proper sense. The ependyma has no continuous tight junctions, so dissolved substances can pass into the extracellular space of the central nervous system.[2],[3]
Which of them lies on the route to the target tissue depends entirely on the route of administration.
Is the blood–brain barrier an obstacle for an infusion?
Yes, in practice it is. Extracellular vesicles can in principle cross the barrier: external work demonstrated active transport by transcytosis and receptor-mediated mechanisms for ten different exosome populations, with transport rates differing by more than tenfold.[4]
That is a qualitative statement, not a quantitative one. The biodistribution data are unambiguous. After intravenous administration, extracellular vesicles are cleared from the circulation within minutes and are taken up predominantly by liver, spleen and lung.[5],[6],[7]
Why does intrathecal application avoid the blood–brain barrier?
Because no barrier lies on this route. At lumbar puncture the secretome is delivered into the lumbar subarachnoid space. From there the cerebrospinal fluid bathes the spinal cord, the nerve roots and the surface of the brain. By way of perivascular spaces it is in convective exchange with the interstitial fluid of the tissue.[9],[10] The procedure itself is described on the page about intrathecal application.
External preclinical work confirms the principle. Intrathecally administered extracellular vesicles distribute widely throughout the central nervous system and are taken up by neurons, in murine and in non-human primate models.[11] Clinically, the route is established in ALS by tofersen, which is given intrathecally and measurably engages its target in the cerebrospinal fluid.[12]
Is intranasal application an alternative?
Not a reliable one in humans. Direct access to the central nervous system is provided only by the olfactory epithelium. In humans it accounts for roughly 3 to 10 per cent of the nasal cavity, while in rats and mice it covers about half of it.[13],[14] This is a principal reason why animal findings on the intranasal route do not translate directly.
The most informative comparison to date comes from a non-human primate model. In macaques, cerebral vesicle uptake was lower after intranasal than after intravenous administration.[7],[15],[16] Intranasal application is non-invasive and can be repeated at will. It preferentially addresses the olfactory bulb, frontobasal regions and the brainstem, and it essentially does not reach the spinal cord.
Does “no barrier” mean the secretome is distributed evenly?
No. The absence of a barrier does not imply uniform distribution. In adults, roughly half a litre of cerebrospinal fluid is produced each day and is continuously drained into the blood, and diffusion from the CSF into the tissue falls off steeply over a few millimetres.[1],[9]
In practice, the structures next to the cerebrospinal fluid are exposed most: the spinal cord, the nerve roots and the surfaces of brainstem and brain. Deep cerebral regions are reached to a lesser and more variable degree.
What does this mean for the treatments at ANOVA IRM?
It means we choose the route according to where the target lies. For conditions of the spinal cord and the motor neurons, the intrathecal route places the preparation where the exposure is highest. For a systemic target, an infusion is the appropriate route, and there the blood–brain barrier remains a limitation.
Reaching the tissue is not the same as clinical benefit. What is known and what is not is set out on the condition pages, for example on the ALS page.
Frequently asked questions
What is the blood–brain barrier?
It is formed by the endothelium of the cerebral capillaries with its tight cell junctions and separates blood from brain tissue. Virtually all large-molecule drugs and the great majority of small-molecule drugs do not cross it to any meaningful extent.
What is the difference between the blood–brain barrier and the blood–CSF barrier?
The blood–brain barrier lies at the cerebral capillaries and separates blood from brain tissue. The blood–CSF barrier lies at the choroid plexus and separates blood from cerebrospinal fluid. The two are anatomically and functionally distinct and are frequently confused.
Is there a barrier between cerebrospinal fluid and brain tissue?
None in the proper sense. The pia mater and the ependyma have no continuous tight junctions, so dissolved substances can pass into the extracellular space of the nervous system. This is a permeable interface, not a barrier.
Does intravenously administered secretome reach the brain at all?
Yes, but to a limited extent. Extracellular vesicles can cross the blood–brain barrier actively by transcytosis; quantitatively this fraction is small compared with uptake by liver, spleen and lung.
How long does the preparation remain in the cerebrospinal fluid?
Not long. In adults, roughly half a litre of cerebrospinal fluid is produced each day and continuously drained into the blood, so uptake into the tissue occurs in the hours following the application.
In ALS or MND the blood–brain barrier is already compromised — would an infusion not suffice?
The barrier is indeed structurally and functionally impaired in ALS.[8] That increases permeability, but to a degree that varies considerably between individuals and cannot be measured in the individual case. Exposure of the nervous system would therefore remain unpredictable.
Does the blood–brain barrier matter in multiple sclerosis (MS)?
Yes, and in a particular way: in MS the barrier is disturbed during relapses, which is why contrast-enhancing lesions appear on MRI. A disturbed barrier is not a reliable route of delivery, so the intrathecal route remains the more predictable one.
Does the blood–brain barrier matter in Parkinson's disease (PD)?
Yes. In PD the target regions lie deep inside the brain, and those are reached least reliably. That applies to an infusion, which has to cross the barrier, and to the cerebrospinal fluid, from which diffusion falls off over a few millimetres.
Does the blood–brain barrier matter in spinal cord injury (SCI)?
Less than elsewhere. The target is the spinal cord, which is bathed directly by the cerebrospinal fluid; it is one of the structures with the highest exposure after an intrathecal application.
Important Pages
Questions people usually ask next. Each is answered in full on its own page.
Affiliations of ANOVA
ANOVA IRM shares its premises in Offenbach with two further institutions owned by Dr. Stehling: the Institut für Bildgebende Diagnostik (IBDO), providing MRI and CT imaging, and the Vitus Prostate Center. Because imaging is carried out in the same building, condition-specific diagnostics — including CT-guided procedures — are performed in-house rather than referred elsewhere. See diagnostics at ANOVA IRM.
References
- [1] Pardridge WM. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 2011;8:7.
- [2] Jiménez AJ, Domínguez-Pinos MD, Guerra MM, et al. Structure and function of the ependymal barrier and diseases associated with ependyma disruption. Tissue Barriers. 2014;2:e28426.
- [3] Serra R, Simard JM. Adherens, tight, and gap junctions in ependymal cells: a systematic review of their contribution to CSF-brain barrier. Front Neurol. 2023;14:1092205.
- [4] Banks WA, Sharma P, Bullock KM, et al. Transport of extracellular vesicles across the blood-brain barrier: brain pharmacokinetics and effects of inflammation. Int J Mol Sci. 2020;21(12):4407.
- [5] Wiklander OPB, Nordin JZ, O'Loughlin A, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4:26316.
- [6] Kang M, Jordan V, Blenkiron C, Chamley LW. Biodistribution of extracellular vesicles following administration into animals: a systematic review. J Extracell Vesicles. 2021;10(8):e12085.
- [7] Driedonks T, Jiang L, Carlson B, et al. Pharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to Macaca nemestrina. J Extracell Biol. 2022;1:e59.
- [8] Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MCO, et al. Impaired blood-brain/spinal cord barrier in ALS patients. Brain Res. 2012;1469:114–128.
- [9] Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes. Sci Transl Med. 2012;4(147):147ra111.
- [10] Lilius TO, Blomqvist K, Hauglund NL, et al. Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs. J Control Release. 2019;304:29–38.
- [11] Lam BWS, Tan M, Gao C, et al. Extracellular vesicles administered via intrathecal injection mediate safe delivery of nucleic acids to the central nervous system for gene therapy. J Extracell Vesicles. 2025;14(7):e70116.
- [12] Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387:1099–1110.
- [13] Gänger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery. Pharmaceutics. 2018;10(3):116.
- [14] Maaz A, Blagbrough IS, De Bank PA. In vitro evaluation of nasal aerosol depositions: an insight for direct nose to brain drug delivery. Pharmaceutics. 2021;13(7):1079.
- [15] Kodali M, Castro OW, Kim DK, et al. Intranasally administered human MSC-derived extracellular vesicles pervasively incorporate into neurons and microglia in both intact and status epilepticus injured forebrain. Int J Mol Sci. 2020;21(1):181.
- [16] Puhar Dominkuš P, Stenovec M, Sitar S, et al. PKH26 labeling of extracellular vesicles: characterization and cellular internalization of contaminating PKH26 nanoparticles. Biochim Biophys Acta Biomembr. 2018;1860(6):1350–1361.
