Transplantation of Encapsulated Bovine Chromaffin Cells in the Sheep Subarachnoid Space: A Preclinical Study for the Treatment of Cancer Pain

Abstract

Chromaffin cells have been shown to release a combination of pain-reducing neuroactive compounds including catecholamines and opioid peptides. The allogeneic transplantation of chromaffin cells in the subarachnoid space has been shown to alleviate pain in various rodent models and possibly in terminal cancer patients. Because of the shortage of human cadaver donor tissue, we are investigating the possibility of transplanting xenogeneic cells in polymer capsules. In this technique, cells are surrounded by a permselective synthetic membrane whose pores are suitably sized to allow diffusion of nutrients, neurotransmitters and growth factors, but restrict the diffusion of the large molecules of the immune system and prevent contact with immunocompetent cells. The encapsulation technique therefore allows transplantation of xenogeneic tissue between species as well as retrieval of transplanted cells. Previously we have reported that encapsulated bovine chromaffin cells survive and alleviate pain in various rodent models. The purpose of the present study was to assess the feasibility of implanting a human sized device in a large animal model. Adrenals from 5 calves were surgically removed; chromaffin cells were isolated from these glands using a collagenase-based digestion-filtration technique. Cells were loaded into acrylic-based tubular (5 cm long, 920 microns wide) permselective capsules attached to silicone tethers. The capsules were maintained in vitro for at least 7 days following the encapsulation procedure. Nicotine evoked release was analyzed in a defined subgroup from each batch. One capsule was then implanted using a guiding cannula system in the lumbar subarachnoid space of each sheep for 4 (n = 5) and 8 (n = 1) wk. All capsules were retrieved intact by gentle pulling on the silicone tether. Except for one capsule, the evoked catecholamine release of the retrieved capsules was in the same range as that of other capsules from the same cohort that had been maintained in vitro. All retrieved capsules were devoid of host cell reaction. Clusters of viable cells dispersed in an alginate immobilizing matrix were observed throughout all the implanted capsules. This study demonstrates the feasibility of transplanting functional encapsulated xenogeneic chromaffin cells into the cerebrospinal fluid of a large animal model using a capsule of appropriate dimensions for human implants. We believe that these results suggest the appropriateness of human clinical trials in patients suffering from refractory terminal cancer pain.

Stability of alginate‐polyornithine microcapsules is profoundly dependent on the site of transplantation

“…While its use is inherently appealing, its success has been precluded by inconsistent performance. Alginate membranes, either alone or in conjunction with a supporting polycationic component, have been used to deliver cell therapy products for the treatment of diabetes, [1][2][3][4][5][6][7][8] chronic pain, 9 hemophilia, 10,11 central nervous system (CNS) disorders, [12][13][14][15][16][17][18][19][20][21][22] and others. Because of the diversity of clinical indications that alginate cell containing capsules can potentially be used for, alginate beads have been implanted into the peritoneum, 23 the subcutaneous space, 24,25 the kidney capsule, 26 the portal circulation, 27,28 the brain parenchyma, 13,22 the spinal cord, 29 the cochlea, 30 and have been used for oral delivery.…”

Chromaffin cell transplants: From the lab to the clinic

“…For example, the administration of an enkephalinase inhibitor in animals with adrenal medullary or chromaffin cell implants in the spinal cord prolonged antinociception (Sagen et al, 1990). Interestingly, host cell reaction was avoided when encapsulated bovine chromaffin cells were transplanted in the sheep subarachnoid space (Joseph et al, 1994). …”

“…In the case of xenografts (i.e., transplantation of bovine chromaffin cells into the rat CNS) immunosuppression is required for the long-term survival of allografts (i.e., cyclosporin A) (Czech et al, 1997;Ortega et al, 1992). The technique that encapsulates chromaffin Life Sciences 91 (2012) [1243][1244][1245][1246][1247][1248][1249][1250][1251] cells is another strategy to avoid immunosuppression in xenogeneic chromaffin cell transplants (Jeon et al, 2006;Joseph et al, 1994).…”

Treatment of spinal cord injury by transplantation of cells via cerebrospinal fluid

“…These findings suggest that the intrathecal microencapsulation of chromaffin cells might be a useful method for treating chronic pain [24] . Also, transplantation of adrenal medullary chromaffin cells into the spinal subarachnoid space has been shown to decrease pain responses in the formalin model of neurogenic inflammatory pain and the chronic constriction injury (CCI) model [25] , as an encapsulating membrane can provide an immunological privileged site enabling successful xenogeneic transplantation [26,27] . This suggests that transplanting functional encapsulated xenogeneic chromaffin cells into the CSF should be useful for human clinical trials in the patients suffered from refractory terminal cancer pain.…”