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

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

A novel self-sintering microparticle-based system for regenerative medicine

The use of injectable scaffolds has raised great interest as they minimise the need for invasive surgery and its associated complications, costs and discomfort to the patient. Furthermore, they can fill cavities of any size or shape as well as being able to deliver a localised therapeutic agent. The aim of this study was to develop an injectable scaffold using PLGA microparticles which may be able to (i) carry cells and/or drugs to a site of injury (ii) be delivered via a narrow bore needle, and (iii) form a scaffold in situ with sufficient mechanical properties. The investigated system exploits a novel in situ solidification mechanism (liquid sintering) whereby the injectable microparticle-based precursors solidify into 3D constructs in response to thermal changes [2]. Thus, we demonstrate that PLGA microparticles incorporated with Triton X-100 are thermally responsive at body temperature (37°C) and may be exploited in regenerative medical applications.Peer reviewe

Life support systems for cell therapies

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Microparticles as tissue engineering scaffolds : manufacture, modification and manipulation

Tissue engineering, a field which focusses on the replacement, repair and regeneration of damaged or diseased tissue by the application of biomaterials, cells and associated biological molecules, has advanced rapidly due to the intense demand for tissue substitutes. A key principle in tissue engineering involves growing the appropriate cells in vitro for the desired application before delivery into the body of a patient. The implantable devices, biological constructs or scaffolds, developed in tissue engineering aim to provide the initial architecture required for supporting the cells as well as define the micro and macrostructure of the final engineered product. Furthermore, these scaffolds may be exploited to release drugs and/or growth factors in a controlled manner, thus facilitating the repair and regeneration of the target tissue. Microparticles, spherical carrier scaffolds, have recently received extensive interest for their potential therapeutic applications in a diverse range of clinical and regenerative medical settings. Not only can these versatile subunits be used as cell culture scaffolds, their innate structure reduces the degradation of encapsulated biologically active molecules and also allows their exploitation as a localised injectable delivery system. The purpose of the present article is to review the tissue engineering applications of these microparticles and to provide a brief overview of the critical factors considered during their formulation and use - including the range of materials used and the different modification protocols and technologies exploited to improve and enhance their mechanical properties and biocompatibility for regenerative medicine.Peer reviewe

The effect of delivery via narrow-bore needles on mesenchymal cells

Aims: Recently, there have been numerous preclinical and human studies investigating the regenerative capacity of cell suspensions following their direct injection into a target organ: the fundamental parameters for successful (clinical) cell therapy. At present, limited data exist in the identification of factors important for the survival of these cells (i.e., morphology, viability and proliferation rates) during and following their ejection via narrow-bore needles. Materials & methods: Primary murine mesenchymal stem cells (mMSCs) were isolated, expanded and processed into a concentrated cell suspension consisting of either HBSS or HBSS supplemented with the antioxidant n-acetyl-cysteine. This suspension was then ejected from a 10 mu l Hamilton syringe, via a variety of bore-sized needles, at different ejection rates. Cell characteristics including viability, spreading and attachment, apoptosis and proliferative ability were then assessed. Results: Following manipulation within a syringe, a decrease in the viability and cell spreading of mMSCs and a concurrent increase in the production of the caspase-3 protein, an early regulatory event in apoptosis, occurs. These detrimental effects were found to be increased when the cells were left in the syringe chamber for increased periods of time, and were similar at 5 mu l/min and 1 mu l/min ejection rates. However, on increasing the needle bore diameter, a significant reduction in these characteristics was observed. By comparison, mMSCs that were left to stand at room temperature (18-20 degrees C), but were not manipulated within a syringe, showed a significantly greater viability compared with manipulated cells. However, cells kept at 4 degrees C demonstrated a decreased viability compared with manipulated cells. When the mMSC were incubated with n-acetyl-cysteine, a known antioxidant, no significant change in caspase-3 production or cell spreading was observed. Conclusions: This study highlights potential parameters, such as minimizing the time period the cells are within the syringe and the use of wider-bore needles, involved in maintaining the high viable cell density required for the delivery of cell suspensions for cell therapy applications.Peer reviewe