Xenotransplantation of cells using biodegradable microcapsules.
BACKGROUND
The use of immunoisolation to protect transplanted cells from the immune system of the host has broad application to the treatment of major diseases such as diabetes and a wide range of other disorders resulting from functional defects of native cell systems. In most cases, limitations in 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 encapsulated 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 needs to be replenished, no surgery will be required to localize and remove the old capsules.


METHODS
Porcine and bovine islets were immobilized in "composite" microcapsules fabricated from alginate and low-relative molecular mass (Mr) poly (L-lysine[PLL]) (Mr exclusion <120 Kd) and implanted into the peritoneum of normal and streptozotocin-induced diabetic rats. In addition to demonstrating long-term islet viability and function, a series of in vitro studies were carried out to determine the permeability and biodegradability of the microcapsules used in the present system.


RESULTS
Xenogeneic islets implanted in nonimmunosuppressed rats remained in excellent condition indefinitely (>40 weeks)(viability was comparable to that of preimplant control specimens). In contrast, no islets survived in uncoated alginate spheres after 2 weeks postimplantation. By changing the concentration of the alginate, it was possible to vary the rate of capsule breakdown in rats from mechanically unstable (outer matrix <0.5-0.75% alginate) to stable for >1 year (> or =1.5% alginate). In addition to in vivo breakdown studies, the biodegradability of the capsular components was verified in vitro using a mixture of tritosomes (enzymes isolated from animal cells).


CONCLUSIONS
We have designed a microcapsule system with controllable biodegradability which allows breakdown and absorption of implants when the cells die or become functionally inactive. These results may have application to other alginate-PLL encapsulation systems. The ability to cross species lines using these biodegradable microcapsules has the potential to expand dramatically the number of patients and the scope of diseases that can be successfully treated with cellular therapy.
Lanza
R P
RP
BioHybrid Technologies Inc., Shrewsbury, Massachusetts 01545, USA. rtla@aol.com
Jackson
R
R
Sullivan
A
A
Ringeling
J
J
McGrath
C
C
Kühtreiber
W
W
Chick
W L
WL
D020341:Absorbable Implants; D000464:Alginates; D000818:Animals; D001672:Biocompatible Materials; D002214:Capsules; D002417:Cattle; D020723:Glucuronic Acid; D006085:Graft Survival / Q000502:physiology; D006603:Hexuronic Acids; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D007515:Islets of Langerhans / Q000503:physiopathology; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D010539:Permeability; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D014183:Transplantation, Heterologous
D000464:Alginates; D001672:Biocompatible Materials; D002214:Capsules; D006603:Hexuronic Acids; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D020723:Glucuronic Acid