Transdermal delivery of therapeutic proteins
Of more recent interest is the use of the intradermal route for systemic delivery of protein- and peptide-based drugs. With
few exceptions, biopharmaceuticals are currently compatible only with injection-based delivery systems including intravenous
(IV), IM, and SC injections. Less-invasive delivery methods such as oral administration of biopharmaceuticals, have been challenged
by the hydrolytic nature of the gastric environment. Delivery via inhalation routes has been elusive because of concerns of poor reproducibility, losses in bioavailability, and the risk of
potential health problems associated with long-term administration regiments (13, 14).
In an effort to improve therapeutic efficacy, as well as to provide a more satisfactory patient experience (hopefully leading
to improved compliance), several transdermal delivery platforms for biopharmaceuticals have been pioneered. As with vaccine
delivery, there are elements unique to the dermis that warrant consideration when considering systemic drug delivery of proteins
As mentioned above, the dermis is highly perfused with both blood and lymphatic capillaries. The lymphatic system is not nearly
as well characterized or as well understood as the microstructure associated with the circulatory system, but it plays a key
role in maintenance and function of the skin and for ID delivery. Lymphatic systems—or lymphatics—are common to higher-order
vertebrates of a size and complexity that require a secondary vascular system to maintain fluid balance. Lymphatics regulate
interstitial fluid pressure; they are also an important conduit of the immune system, trafficking antigen presenting cells
to the lymph nodes as well as providing a corridor for the migration of T- and B-cells (3, 7, 15–6).
The distal capillaries are the smallest features of the lymphatic system and stretch into the upper layers of the dermis.
Structurally, the distal capillaries are arranged vertically within the upper dermis and drain unidirectionally toward collection
vessels in the lower dermis. The distal capillaries are 10–70 µm in diameter and have thin walls made up of a single nonfenestrated
membrane of endothelial cells; adjacent cells often overlap. Figure 3 shows the distribution of lymphatic capillaries in the
Figure 3: Cross-section schematic depicting epidermis (red), dermis (pink), subcutaneous adipose (yellow), and intramuscular
tissues (tan) with lymphatic capillaries shown in green (first panel), blood capillaries shown in red and blue (second panel),
and the two systems overlaid (third panel). In the upper dermis, the capillaries extend normal to the surface of the skin;
in the lower dermis, subcutaneous and intramuscular tissue, the capillaries are shown in cross section, running parallel to
the skin's surface. (FIGURE 3 IS ADAPTED FROM HANSEN ET AL. (REF 58).; FIGURE 3 IS BY P. BOHACEK/COURTESY OF AUTHOR)
In lymphatic capillaries, segments of the overlapping endothelial cells are tethered to collagen fibers by anchoring filaments
that prevent the thin walls of the capillaries from collapsing. These spring-like filaments allow the capillaries to go from
a state of near collapse to one of stretched expansion in response to increases in interstitial fluid pressures. The combination
of the anchoring filaments and the overlapping arrangement of the endothelial cells create flap valves along the capillaries,
which readily open to accept interstitial fluid, macromolecules, and particulates in response to local pressure changes (17–19).
This mechanism is illustrated in Figure 4.
Figure 4: Representation of the transport mechanisms for proteins and particulates (green dots) into lymphatic capillaries.
Small red arrows indicate a minor intracellular transport route; bold red arrows indicate the dominant intercellular transport
route, wherein increases in interstitial pressure force open untethered flap valves between overlapping endothelial cells.
The pink shapes represent anchoring filaments.
Tracer studies conducted in guinea pigs and mice indicate that this intercellular transport mechanism is the main mechanism
whereby proteins and particulates are cleared from the interstitial space (5, 18–19).
Larger collecting lymphatic vessels, situated horizontally, reside in the lower dermis (5, 17). The walls of the collection
vessels are thicker than the capillaries. These vessels contain valves to prevent the backflow of lymph (3, 17, 19). Unlike
the distal capillaries, the walls of the collecting lymph vessels include a thin layer of smooth muscles that propel the lymph
through the vessels to the local lymph nodes for filtration and, ultimately, to the main lymphatic ducts for entry into the