No abstract

Cell microencapsulation continues to hold significant promise for biotechnology and medicine. The controlled, and continuous, delivery of therapeutic products to the host by immunoisolated cells is a potentially cost-effective method to treat a wide range of diseases. Although there are several issues that need to be addressed, including capsule manufacture, properties and performance, in the past few years, a stepwise analysis on the essential obstacles and limitations has brought the whole technology closer to a realistic proposal for clinical application. This paper summarizes the current situation in the cell encapsulation field and discusses the main events that have occurred along the way.

A potentially cost-effective strategy for gene therapy of hemophilia B is to create universal factor IX-secreting cell lines suitable for implantation into different patients. To avoid graft rejection, the implanted cells are enclosed in alginate-polylysine-alginate microcapsules that are permeable to factor IX diffusion, but impermeable to the hosts' immune mediators. This nonautologous approach was assessed by implanting encapsulated mouse myoblasts secreting human factor IX into allogeneic mice. Human factor IX was detected in the mouse plasma for up to 14 days maximally at approximately 4 ng/mL. Antibodies to human factor IX were detected after 3 weeks at escalating levels, which were sustained throughout the entire experiment (213 days). The antibodies accelerated the clearance of human factor IX from the circulation of the implanted mice and inhibited the detection of human factor IX in the mice plasma in vitro. The encapsulated myoblasts retrieved periodically from the implanted mice up to 213 days postimplantation were viable and continued to secrete human factor IX ex vivo at undiminished rates, hence suggesting continued factor IX gene expression in vivo. Thus, this allogeneic gene therapy strategy represents a potentially feasible alternative to autologous approaches for the treatment of hemophilia B.

Cell encapsulation is a bioengineering technology that provides live allogeneic or xenogeneic cells packaged in a semipermeable immune-isolating membrane for therapeutic applications. The concept of cell encapsulation was first proposed almost nine decades ago, however, and despite its potential, the technology has yet to deliver its promise. The few clinical trials based on cell encapsulation have not led to any licensed therapies. Progress in the field has been slow, in part due to the complexity of the technology, but also because of the difficulties encountered when trying to prevent the immune responses generated by the various microcapsule components, namely the polymer, the encapsulated cells, the therapeutic transgenes and the DNA vectors used to genetically engineer encapsulated cells. While the immune responses induced by polymers such as alginate can be minimized using highly purified materials, the need to cope with the immunogenicity of encapsulated cells is increasingly seen as key in preventing the immune rejection of microcapsules. The encapsulated cells are recognized by the host immune cells through a bidirectional exchange of immune mediators, which induce both the adaptive and innate immune responses against the engrafted capsules. The potential strategies to cope with the immunogenicity of encapsulated cells include the selective diffusion restriction of immune mediators through capsule pores and more recently inclusion in microcapsules of immune modulators such as CXCL12. Combining these strategies with the use of well-characterized cell lines harboring the immunomodulatory properties of stem cells should encourage the incorporation of cell encapsulation technology in state-of-the-art drug development.