Significant progress has been made during the past decade towards the clinical adoption of cell-based therapeutics. However, existing cell-delivery approaches have shown limited success, with numerous studies showing fewer than 5% of injected cells persisting at the site of injection within days of transplantation. Although consideration is being increasingly given to clinical trial design, little emphasis has been given to tools and protocols used to administer cells. The different behaviours of various cell types, dosing accuracy, precise delivery, and cell retention and viability post-injection are some of the obstacles facing clinical translation. For efficient injectable cell transplantation, accurate characterisation of cellular health post-injection and the development of standardised administration protocols are required. This review provides an overview of the challenges facing effective delivery of cell therapies, examines key studies that have been carried out to investigate injectable cell delivery, and outlines opportunities for translating these findings into more effective cell-therapy interventions.

ObjectivesThis study focuses on the effect of the injection administration process on a range of cell characteristics.MethodsEffects of different ejection rates, needle sizes and cell suspension densities were assessed in terms of viability, membrane integrity, apoptosis and senescence of NIH 3T3 fibroblasts. For ratiometric measurements, a multiplex assay was used to verify cell viability, cytotoxicity and apoptosis independent of cell number. Co‐delivery with alginate hydrogels and viscosity‐modifying excipients was also assessed.Key findingsEjections at 150 μl/min resulted in the highest percentage of dose being delivered as viable cells among ejection rates tested. The difference in proportions of apoptotic cells became apparent 48 h after ejection, with proportions being higher in samples ejected at slower rates. Co‐delivery with alginate hydrogels demonstrated a protective action on the cell payload.ConclusionsThis study demonstrates the importance of careful consideration of administration protocols required for successful delivery of cell suspensions, according to their nature and cellular responses post‐ejection.

Dental pulp tissue represents a source of mesenchymal stem cells that have a strong differentiation potential towards the osteogenic lineage. The objective of the current study was to examine in vitro osteogenic induction of dental pulp stem cells (DPSCs) cultured on hydrogel scaffolds derived from decellularized bone extracellular matrix (bECM) compared to collagen type I (Col-I), the major component of bone matrix. DPSCs in combination with bECM hydrogels were cultured under three different conditions: basal medium, osteogenic medium and medium supplemented with growth factors (GFs) and cell growth, mineral deposition, gene and protein expression were investigated. The DPSCs/bECM hydrogel constructs cultured in basal medium showed that cells were viable after three weeks and that the expression of runt-related transcription factor 2 (RUNX-2) and bone sialoprotein (BSP) were significantly upregulated in the absence of extra osteogenic inducers compared to Col-I hydrogel scaffolds. In addition, the protein expression levels of BSP and osteocalcin were higher on bECM with respect to Col-I hydrogel scaffolds. Furthermore, DPSCs/bECM hydrogels cultured with osteogenic or GFs supplemented medium displayed a higher upregulation of the osteo-specific markers compared to Col-I hydrogels in identical media. Collectively, our results demonstrate that bECM hydrogels might be considered as suitable scaffolds to support osteogenic differentiation of DPSCs.

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As the number of clinical trials exploring cell therapy rises, a thorough understanding of the limits of cell delivery is essential. We used an extensive toolset comprising various standard and multiplex assays for the assessment of cell delivery postejection. Primary human mesenchymal stem cell (hMSC) suspensions were drawn up into 100-µl Hamilton syringes with 30- and 34-gauge needles attached, before being ejected at rates ranging from 10 to 300 µl/minute. Effects of ejection rate, including changes in viability, apoptosis, senescence, and other key aspects of cellular health, were evaluated. Ejections at slower flow rates resulted in a lower percentage of the cell dose being delivered, and apoptosis measurements of samples ejected at 10 µl/minute were significantly higher than control samples. Immunophenotyping also revealed significant downregulation of CD105 expression in samples ejected at 10 µl/minute (p < .05). Differentiation of ejected hMSCs was investigated using qualitative markers of adipogenesis, osteogenesis, and chondrogenesis, which revealed that slower ejection rates exerted a considerable effect upon the differentiation capacity of ejected cells, thereby possibly influencing the success of cell-based therapies. The findings of this study demonstrate that ejection rate has substantial impact on the percentage of cell dose delivered and cellular health postejection.