The level at which implanted sensors and sampling devices maintain their calibration is an important research area. In this work, microdialysis probes with identical geometry and different membranes, polycarbonate/polyether (PC) or polyethersulfone (PES), were used with internal standards (vitamin B12 (MW 1355), antipyrine (MW 188) and 2-deoxyglucose (2-DG, MW 164)) and endogenous glucose to investigate changes in their long-term calibration after implantation into the subcutaneous space of Sprague-Dawley rats. Histological analysis confirmed an inflammatory response to the microdialysis probes and the presence of a collagen capsule. The membrane extraction efficiency (percentage delivered to the tissue space) for antipyrine and 2-DG was not altered throughout the implant lifetime for either PC- or PES-membranes. Yet, Vitamin B12 extraction efficiency and collected glucose concentrations decreased during the implant lifetime. Antipyrine was administered i.v. and its concentrations obtained in both PC-and PES-membrane probes were significantly reduced between the implant day and seven (PC) or 10 (PES) days post implantation suggesting that solute supply is critical for in vivo extraction efficiency. For the low molecular weight solutes such as antipyrine and glucose, localized delivery is not affected by the foreign body reaction, but recovery is significantly reduced. For Vitamin B12, a larger solute, the fibrotic capsule formed around the probe significantly restricts diffusion from the implanted microdialysis probes.
Structural complexity of biological drug products presents an analytical challenge in terms of early detection of aggregation and/or degradation. In the present study, Raman and Raman optical activity (ROA) were evaluated for their sensitivity to detect heat-induced molecular instability in an Immunoglobulin G4 subclass therapeutic monoclonal antibody present in its formulation matrix. The therapeutic antibody was subjected to heat stress at 50°C and was analyzed at various time points up to 1 month. The current results suggest that Raman and ROA are sensitive to early-stage detection of heat-induced instability of the antibody, in which significant changes could be observed at 1 week of stress. ROA could provide early detection of the subtle differences at the tertiary structure level in a heat-stressed monoclonal antibody and Raman/ROA spectra could provide early detection in secondary structural changes as well.
Modulation of the foreign body reaction is considered to be an important step toward creation of implanted sensors with reliable long-term performance. In this work, microdialysis probes were implanted into the subcutaneous space of Sprague-Dawley rats. The probe performance was evaluated by comparing collected endogenous glucose concentrations with internal standard calibration (2-deoxyglucose, antipyrine, and vitamin B12). Probes were tested until failure, which for this work was defined as loss of fluid flow. In order to determine the effect of fibrous capsule formation on probe function, monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2) was delivered locally via the probe to increase capsule thickness and dexamethasone 21-phosphate was delivered to reduce capsule thickness. Probes delivering MCP-1 had a capsule that was twice the thickness (500-600 μm) of control probes (200-225 μm) and typically failed 2 days earlier than control probes. Probes delivering dexamethasone 21-phosphate had more fragile capsules and the probes typically failed 2 days later than controls. Unexpectedly, extraction efficiency and collected glucose concentrations exhibited minor differences between groups. This is an interesting result in that the foreign body capsule formation was related to the duration of probe function but did not consistently relate to probe calibration.
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