In the dermis, the blood capillaries are situated similarly to the lymphatic capillaries, however, there are significant structural
differences between the two. Instead of the blind ends characteristic of lymphatic capillaries, the blood capillaries in the
upper dermis are arranged in vertical loops that carry blood both to and from the upper regions of the dermis. The cell walls
of blood capillaries are thicker than those on the lymphatic capillaries and are characterized by a continuous basement membrane.
The membrane is permeable to fluid exchange and allows for transport from the interstitial fluid of some small, lipophilic
molecules; however, the membrane is continuous (with no flap valves) and is restrictive to the transfer of macromolecules
or particulates. Finally, fluid movement within the capillaries is powered by the continuous beating of the heart; lymphatic
fluid movement is governed by a variety of internal and external factors.
It is widely acknowledged that proteins larger than 16 kD are generally cleared from the interstitium via the lymphatics (20–22). The clearance is facilitated by the flap valves and lymphatic fluid flow that is driven by differences
in interstitial pressure. Efforts to create macromolecular pro-drugs by tethering a small molecule to a macromolecular carrier,
or with liposomal encapsulation systems, are aimed at increasing the size of the drug-carrier system and thus, increase uptake
by the lymphatics (22–25).
In 1990, Supersaxo et al. used a sheep model to demonstrate a correlation between molecular weight and lymphatic uptake for
molecules injected subcutaneously. This group proposed that molecules larger than 16 kD are primarily absorbed by the lymphatics
(20, 26). Figure 5 shows this relationship.
Figure 5: Experimental data demonstrating the dependence of lymphatic uptake on molecular weight. FUdR is Floxuridine; IFN-alpha-2a
is interferon-alpha-2; and hGH is human growth hormone. (FIGURE 5 IS REPRINTED WITH PERMISSION FROM JOHN WILEY & SONS (REF.
Figure 6 shows the results of a study conducted by Skobe et al., where a high molecular weight FITC-dextran was injected intradermally
into mouse skin. Lymphatic vessels (indicated by the white arrow) take up the high molecular weight, fluorescently-labeled
molecules, while a nearby blood vessel (white arrowhead) has not.
Figure 6: Enhanced lymphatic uptake of intradermally delivered fluorescently-labeled macromolecule. Arrow shows uptake in
lymphatic capillary; arrowhead indicates nearby blood vessel. (FIGURE 6 IS REPRINTED WITH PERMISSION FROM MACMILLAN PUBLISHERS
In a 2010 imaging study, Harvey et al. demonstrated fast lymphatic uptake upon intradermal administration. Within 20 s of
intradermal injection, a low molecular weight fluorescent dye illuminated a lymph node 40 cm from the injection site. A similar
injection into the subcutaneous tissue stayed localized with no visual evidence of lymphatic uptake during the observation
period associated with the study (27).
Given the increased density of lymphatic capillaries in the dermis, along with the increased interstitial pressure associated
with intradermal delivery, it may be that the uptake of biopharmaceuticals is further favored by the lymphatics upon intradermal
Enhanced lymphatic uptake in the dermis may be further evidenced in comparative pharmacokinetic studies conducted between
intradermal and SC or IM delivery. Several groups have reported intradermal pharmacokinetic (PK) profiles in which drug in
the plasma reach maximal levels (Tmax) earlier following ID than IM or SC delivery. Maximal drug concentrations in plasma
(Cmax) are also higher following ID delivery, and in some cases, bioavailability is also higher than when the same amount
of protein is injected into deeper tissue (as is the case with both IM and SC delivery methods) (27–29). These PK characteristics
are consistent with more pronounced lymphatic uptake and are evident even for biopharmaceuticals such as insulin and parathyroid
hormone 1-34 (PTH) that are well below the 16 kD equilibrium proposed for lymphatic absorption following subcutaneous uptake.
Enhanced lymphatic uptake via intradermal delivery may offer therapeutic advantages over conventional injection routes. A
PK profile that achieves a higher, sharper Cmax for delivery of compounds, including hormones, such as PTH and human growth
hormone (hGH) may more closely mimic endogenous secretions in healthy subjects (30, 31). Faster delivery for compounds such
as insulin may provide the opportunity for more responsive therapeutic interventions for diabetics, with short- and long-term
benefits to patient health. Analogous to the dose-sparing potential for intradermally delivered vaccines, biopharmaceuticals
may also be more rapidly and completely taken up into the lymphatic system. Intradermal delivery may therefore offer higher
therapeutic efficiency for exceptionally large biopharmaceuticals than can SC or IM delivery. These large molecules are often
difficult and costly to manufacture, so there may exist a considerable cost advantage to administering a reduced dose intradermally
and that still achieves the same therapeutic endpoints associated with a higher dose delivered via subcutaneous injection.
Lymphatic delivery has long been the focus of targeted delivery efforts for tumor therapies associated with various cancers,
as regional lymph-node dissemination is the first step in the metastasis of several cancers (32, 33). Furthermore there exists
the possibility of minimiziing toxic side effects associated with systemic delivery of chemotherapies targeted at the lymphatics
if a smaller dose could be administered intradermally for preferential uptake into the lymphatic system. Currently, IV administration
of these drugs results in widespread systemic dispersion with only minimal quantities of drugs reaching the lymph nodes (34).
In part because of advances in intradermal drug delivery technologies, the potential therapeutic benefits associated with
intradermal delivery are just starting to be realized. The remainder of this article will describe some of the main intradermal
delivery techniques and devices. Power- and jet-injectors and iontophoretic devices will not be discussed; these technologies
are reviewed elsewhere (35).