Tissue Responses At A Subcutaneous Injection Site Events Stimulated by Needle Penetration at Injection

Following withdrawal, large-diameter needles can produce a wound that is not immediately closed by the elastic nature of the epidermis; use of large-diameter needles can result in the loss of some material leaving the SC injection site because of back pressure. This is one reason small gauge needles are preferred for SC injections. Another reason is that larger needles are likely to come in contact with a greater number of pain-registering nerves than a smaller needle. Further, needle lengths used for SC injections are specifically selected to restrict accidental delivery to sites deep to this loose connective tissue compartment. Overall, small gauge needles of specific lengths are the standards for delivering protein and peptide therapeutics to the SC site to reduce the extent of pain on injection and minimize the chance of missing the SC space.

Under nonpathological conditions, the SC space is relatively devoid of blood-derived cells and protease/peptidase activities. The act of delivering a protein or peptide via an injection to the SC space amounts to introduction of a transient wound in the skin. Unless a very large needle is used, the opening in the epidermis and dermis produced by the needle tract closes within seconds. The act of needle penetration, however, initiates processes associated with wound repair, the resolution of which involves activation of cell- and protease-based mechanisms. Although this discussion is not intended to focus on the complexities of events involved in wound repair mechanisms, a brief summary highlighting some aspects of these events is helpful in appreciating potential implications on PK, PD, and metabolism of an injected protein or peptide.

Typically, the actions of serum proteases and peptidases that leak from capillary beds into the SC space are restrained through the presence of inhibitory elements; pathological conditions can arise from an imbalance of these inhibitor/protease functions (21). Although a number of proteases and pepti-dases can be present in the SC space, additional activities may enter or become activated within this space by an SC injection. For example, in response to changes in physiological conditions, cells of the ECM can secrete proteases, such as serine and threonine proteases as well as matrix metalloproteinases, that induce the local release of growth factors from an ECM depot (22). Thus, although the SC space is not normally enriched in proteolytic activities, this can change in response to events associated with the injection of a protein or peptide therapeutic.

Further, a number of specialized cells (discussed below) associated with the immune system are resident within the SC space; these cells guard against pathogen entry that might occur as a result of skin wounding. Once activated by signals associated with skin wounding, these resident cells could also secrete a variety of protease activities that function as part of the innate immune response. Thus, the repertoire of protease activities in the SC space can be shifted and augmented within the interstitial space by inflammatory processes (23). Additionally, it is possible that other factors released by the cells associated with the innate immune response might affect vascular permeability (discussed in detail later). Together, these factors and their affects on protease and pepti-dase activities could affect PK and PD of a protein or peptide therapeutic injected into the SC space through metabolic events.

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