Dose Control with Cell Lines Used for Encapsulated Cell Therapy

Abstract

Cell therapy-use of cells to deliver active factors-is an emerging technique in treatment of neurodegenerative disease. Successful devices maintain cell viability and functionality over extended implant periods. Use of dividing cell lines to deliver therapeutic factors has been studied extensively. One emerging issue is the tendency of cells to continue proliferation within the intracapsular environment-potentially outstripping nutrient supply. This work presents a method of controlling proliferation and delivering therapeutic molecules within a dose range. The method entails encapsulation into a hollow fiber device of discrete numbers of cell-containing microcarriers. Proliferation control is attained by embedding cell-containing microcarriers in nonmitogenic hydrogels. PC-12 cells secreting L-dopa and dopamine was the model cell line tested. Feasibility of the method in controlling growth of normally rapidly dividing cells in the intracapsular environment was demonstrated in vitro and in vivo. Control nonmicrocarrier PC-12 cell devices had approximately fourfold greater expansion in cell number compared to experimental microcarrier-containing devices over 4 weeks in vitro and in vivo after implant into rat striatum. Ability to control dose released over a several-fold range was demonstrated with encapsulated PC-12 cells delivering neurotransmitters and C2C12 mouse myoblast cells delivering neurotrophic factors (CNTF).

Therapy with Cell Encapsulation for Substitution of Organ Function and Tumor Treatment

“…[37] One way is to work with preformed hollow tubes (hollow fibers), [38] which can be filled and sealed. [39] Such containments will not be as round as a capsule formed with alginate or cellulose sulfate; however, they can be as small as these (Ø 0.1-0.5 mm). Furthermore, hollow fibers can also be refilled from the outside, e.g., when treating CNS disease such as Parkinson's disease or brain tumors [40] or substituting for liver function.…”

“…[72] Another indication is the so-called GDEPT in which the encapsulated cells express an enzyme that converts a prodrug administered otherwise (e.g., systemically) at the site of the encapsulated cells. [3] The major problem of all cell therapy involving the transfer of living cells has been the tendency of the cells to proliferate further and divide, [39] thus potentially endangering the containment by cracking or breaking. Cells can grow beyond the transplantation site and form tumors.…”

“…Cells can grow beyond the transplantation site and form tumors. [73] Therefore, methods have been devised to ensure minimalization of this phenomenon, [39] e.g., by design of special matrices to embed the cells to be encapsulated. [74] The open design of hollow fibers has in part circumvented this problem.…”

Intracompartmental Delivery of CNTF as Therapy for Huntingtons Disease and Retinitis Pigmentosa

“…But without them, the conditions optimal for successful cell encapsulation will remain speculative. Some efforts are ongoing in this area and a recent study raised the interesting possibility that dose control for dividing cells could be accomplished with the use of cell-containing microcarriers in nonmitotic hydrogels [Li et al, 1999]. In this context, the studies by Thanso and colleagues [2004] demonstrating longterm, stable secretion of CNTF from various cell lines is an avenue of dose regulation that deserves greater attention.…”

In Vitro Systems for Tissue Engineering

“…A similar strategy has also been pursued for the genetic engineering of anti‐angiogenic factor‐secreting cells 85. The use of non‐mitogenic hydrogels has also been employed to control the level of theraputic molecules emanating from cells encapsulated in hollow fibers 86. The idea in this case was that fewer cells would impose a lesser drain on local nutrient supplies, although alternate methods to combat this problem currently exist.…”