Chronic pain of different etiologies affects brain structure and function [1]. It may cause other symptoms or conditions, including depression and anxiety, and may also contribute to decreased physical activity given the apprehension of exacerbating pain [2]. Despite recent advances in our understanding of chronic pain mechanisms and normal nociceptive transmission, the management of chronic pain, particularly neuropathic pain, is still far from resolved with currently available therapeutic regimens. Although many effective treatments are available, a number of adverse effects that interfere with the quality of life may be associated with treatment, and a significant number of patients obtain no relief from these treatments. Therefore, chronic pain is a major medical and societal problems resulting in enormous financial costs [3].

Transplanting cells that secrete neuroactive substances with analgesic properties into the central nervous system (CNS) may have therapeutic potential for the long-term treatment of chronic pain [4-7]. Cell transplantation could provide analgesic effects similar to neuraxial drug delivery pumps such as the secretion of pain-reducing neuroactive substances at optimal sites and constant level, while overcoming problems of pump refilling and maintenance. In addition, these cell-based approaches targeted to the CNS could alleviate most systemic side effects. Therefore, the selection of appropriate bioengineered cells as biological mini pumps can provide permanent management of chronic pain. This review focuses on the role of cell-based therapy in the management of chronic pain.

Cell transplants for pain are based on the concept of descending inhibitory modulation of sensory information. Descending inhibitory tracts from cell bodies in the periaqueductal gray, reticular formation, and nucleus magnus project to the dorsal horn. These inhibitory tracts contain a variety of neurotransmitters, including catecholamines and opioids, which play an important role in nociceptive responses [8,9]. Chromaffin cells [4-7], neural precursor cells [10], mesenchymal stem cells [11], and genetically engineered cells [12] can secrete neuroactive materials, including catecholamines, opioid peptides, and other neuropeptides with anti-nociceptive properties. Intrathecal transplantation of these cells induces analgesia in animal pain models.

One of the biggest issues for organ transplantation is the shortage of donor tissues or organs. The low number of available grafts requires the use of xenogenic non-human donors, but the transplants undergo immunological rejection, limiting their survival. In addition, the continuous use of immunosuppressive agents to prevent immunological rejection often causes side effects, such as bacterial or viral infection and carcinogenesis. Analgesic effects correlate with graft viability and output [6,7,13], and xenogenic grafts are frequently rejected. Therefore, protecting grafts from immunological responses by encapsulating them within a semipermeable membrane using biocompatible materials allows for immunoisolation, which permits the inward diffusion of small molecule nutrients and oxygen, and outward diffusion of therapeutic material produced by implants, but preventing host immune system responses and improving long-term graft survival without immunosuppressants [5-7].

One common design for microencapsulation involves enclosing cells within the lumen of a semipermeable membrane or flat sheet membrane of polyacrylonitrile/polyvinylchloride fiber [13]. For macroencapsulation, cells are usually suspended in a matrix within a hollow fiber membrane. The open ends of the hollow fiber are sealed, thereby forming a capsule within which the cells reside. The advantages of this technique include stability of the implant and ease of retrieval. However, the relatively thick fiber membrane is disadvantageous for cell viability and the efficient release of neuroactive materials, because there is a relatively large diffusion distance across the membrane. The loss of cell viability, in particular, severely limits the usefulness of macrocapsules [13]. This low grafting rate of cells transplanted and their consequent poor functions often cause low therapeutic efficacy of cell transplantation. Cells must have a suitable environment to overcome these problems. Microcapsules are much smaller, durable, and typically have a larger surface to volume ratio that is advantageous for the bi-directional diffusion of nutrients, oxygen, and bioactive materials, compared to macrocapsules. Therefore, microcapsules are more effective for the delivery of analgesic substances by transmembrane diffusion than macrocapsules [5-7]. In addition, the dimensions of microcapsules can be scaled easily to suit different species and implantation sites, although they are fragile and cannot be retrieved easily.

Cell based treatment offers certain benefits in controlled, safe, long-term delivery of analgesic molecules in experimental cell-based therapies. In addition, novel technologies such as encapsulation and engineered cell lines hold promise for future applications. Initial clinical trials have been generally encouraging, although evidence for translation into clinical use in humans is limited. Together, these studies suggest that cell transplantation is a potentially valuable complementary approach in the therapeutic management of chronic pain.