Translation of Cell Therapies to the Clinic: Characteristics of Cell Suspensions in Large-Diameter Injection Cannulae

Abstract

With the use of cell replacement therapies as a realistic prospect for conditions such as Parkinson's and Huntington's diseases, the logistics of the delivery of cell suspensions to deep brain targets is a topic for consideration. Because of the large cannulae required for such procedures, we need to consider the behavior of cell suspensions within the cannulae if we are to ensure that the injected cells are distributed as intended within the target tissue. We have investigated the behavior of primary embryonic cell suspensions of neural tissue, in cannulae of different diameters, using a protocol designed to mimic the handling and injection of cells during clinical application. Internal cannula diameter had a large effect on the distribution of cells during their dispensation from the syringe. In vertical or near vertical cannulae, cells settled toward the tip of the needle, and were dispensed unevenly, with the majority of cells emerging in the first 10-20% of the injectate. In horizontal or near-horizontal cannulae, we observed the opposite effect, such that few cells were dispensed in the first 80% of the injectate, and the majority emerged in the final 10-20%. Use of a glass cannula showed that the results obtained using the horizontal cannula were caused by settling and adherence of the cells on the side of the cannulae, such that during dispensation, the overlying, cell-free solution was dispensed first, prior to the emergence of the cells. We show that the behavior of cells in such cannulae is affected by the cannula diameter, and by the material of the cannula itself. In horizontal cannulae, uneven expulsion of cells from the needle can be ameliorated by regular rotation of the cannula during the procedure. We discuss the potential impact of these observations on the translation of cell therapies to the clinic.

Translational considerations in injectable cell-based therapeutics for neurological applications: concepts, progress and challenges

“…Material employed for construction of delivery device Recent studies have shown that cells may be retained in the delivery device, 60 , 75 with this effect being more pronounced in glass cannulas than in metal. 75 Whether the adherence of the cells to the walls of the syringe/cannula is due to chemical, physical or charge effects has not been studied, but all of these might possibly be manipulated to decrease adhesion and settling. 75 In addition, coating the inner surface of the needle/catheter with proteins may reduce cell adhesion to the device.…”

“… 75 Whether the adherence of the cells to the walls of the syringe/cannula is due to chemical, physical or charge effects has not been studied, but all of these might possibly be manipulated to decrease adhesion and settling. 75 In addition, coating the inner surface of the needle/catheter with proteins may reduce cell adhesion to the device. 76 In addition to possible adherence to device materials, cells may encounter residual trace amounts of manufacturing agents that could induce apoptosis or undesired differentiation.…”

“…The use of hydrophilic and siliconised coatings on internal walls of the cannula has also been suggested to decrease friction between the needle and tissue in vivo. 75 Although glass cannulas present several advantages, including higher precision and minimal penetration injuries, 21 glass may not be sufficiently rigid to endure injection pressure. Novel materials such as electroactive polymers and magnetorheological elastomers 77 show promise for the development of tailored needles whose rigidity could be adjusted by current, magnetic field or temperature.…”

Critical location of cell viability loss during the cell injection process in hepatocyte transplantation using a rectangular microchannel model

“…Studies have reported the effects of cell injection by a needle or cannula on the viabilities of embryonic rat brains cells (Torres et al, 2015), fibroblasts (Amer, et al, 2015), mesenchymal stem cells (Agashi, et al, 2009;Heng et al, 2009;Walker et al, 2010;Mamidi et al, 2012;Amer, et al, 2016), neural stem cells (Rossetti et al, 2015) and hepatocytes (Meyburg et al, 2009a). Improvement of cell injection is desirable to increase the quantities of functional live cells delivered to the target organ, and mechanistic investigation of the phenomena may facilitate development of the cell injection process.…”

Interneuron transplantation: a prospective surgical therapy for medically refractory epilepsy

“…Additionally, technical aspects of cellular delivery must be further resolved to optimize future clinical applications. 2 Numerous procedural factors determine the successful targeting of cells and biological agents into the nervous system, including cannula material and shape, 32,61,72 cell suspension vehicle, 51 cell density, 51 injection rate, 32 injection volume, 19 and tissue compliance at the injection site. 18 These parameters must be accounted for and evaluated in future preclinical studies of interneuron transplantation.…”