Xenotransplantation of cells using biodegradable microcapsules

Background. The use of immunoisolation to protect transplanted cells from t he immune system of the host has broad application to the treatment of majo r diseases such as diabetes and a wide range of other disorders resulting f rom functional defects of native cell systems, In most cases, limitations i n functional cell longevity will necessitate periodic replenishment of the cells. We describe a hydrogel-based microcapsule that breaks down at a rate that can be adjusted to correspond to the functional longevity of the enca psulated cells. These injectable capsules can be engineered to degrade over several weeks to months for short-term drug delivery, or to remain intact and immunoprotective for more extended periods. When the supply of cells ne eds to be replenished, no surgery will be required to localize and remove t he old capsules. Methods. Porcine and bovine islets were immobilized in "composite" microcap sules fabricated from alginate and low-relative molecular mass (M-r) poly ( L-lysine[PLL]) (M-r exclusion <120 Kd) and implanted into the peritoneum of normal and streptozotocin-induced diabetic rats. In addition to demonstrat ing long-term islet viability and function, a series of in vitro studies we re carried out to determine the permeability and biodegradability of the mi crocapsules used in the present system. Results. Xenogeneic islets implanted in nonimmunosuppressed rats remained i n excellent condition indefinitely (>40 weeks)(viability was comparable to that of preimplant control specimens). In contrast, no islets survived in u ncoated alginate spheres after 2 weeks postimplantation. By changing the co ncentration of the alginate, it was possible to vary the rate of capsule br eakdown in rats from mechanically unstable (outer matrix <0.5-0.75% alginat e) to stable for >1 year (greater than or equal to 1.5% alginate). In addit ion to in vivo breakdown studies, the biodegradability of the capsular comp onents was verified in vitro using a mixture of tritosomes (enzymes isolate d from animal cells). Conclusions. We have designed a microcapsule system with controllable biode gradability which allows breakdown and absorption of implants when the cell s die or become functionally inactive. These results may have application t o other alginate-PLL encapsulation systems, The ability to cross species li nes using these biodegradable microcapsules has the potential to expand dra matically the number of patients and the scope of diseases that can be succ essfully treated with cellular therapy.