ReviewCell microencapsulation technology :

Towards clinical applications

Authors:Ainhoa Murua, Aitziber Portero et al, 2008

Journal of Controlled ReleaseJournal homepage: www.elsevier.com/locate/jconrel

Presented by:Oscar Leonardo Mosquera

Electronic Engineer

Outline

● Introduction● Cell encapsulation technology● Biomaterials● Requirements of the technology● The versatility of cell encapsulation

technology● Concluding remarks. Future directions and

challenges.

Introduction

Pharmacokineticsproperties

Delivery process

Release the therapeutically active

molecule at the level and dose it is needesd and during the optimal time

Cell uencapsulation

Immobilization of cells,polymeric matrix,

Semipermeable membrane

Encapsulated cellsAre isolated from the Host immune system

Long-term release oftherapeutics Exchange of nutrients

Diabetes, cancer, CNS Diseases and endocrinology

Disorders among others

Delivery of drugs via Intravascular, subcutaneous

Pulmonary, ophtalmic, And oral routes

Ideal system:

- achieve an effective drug Concentration at the target

Tissue for an extended Period of time.

-minimize systemic exposure

-Provide tight control over theDevice in case of side-effects

Versatility

Based on

Cell encapsulation technology

Immobilization of cellsWithin a semipermeable

membrane

Difussion of Nutrients

-Mechanical stress-host´s immune system

protection

Reduction or even lack ofAdministration of

immunosuppresants

u-encapsulation of cells Instead of

therapeutics products

Delivery for a longer Time as cell release

The products continously

Immobilization of cells Shows important

Advantages

Transplantationof non human

cells

Genetically modified cells

Sustained and Controlled Delivery of´de novo´

If the device

Is borken?

If cells manage to

exit the device

Cells releasethe products continously

Express any desired proteinunmodify host

genome

MorePhisiological

concentrations

Toxicity by a quick deliveryof high [drug]

could be avoided

host´s immuneSystem might

attack

A. Murua et al. / Journal of Controlled Release 132 (2008) 76–83

Biomaterials

● Many different materials are employed to encapsulate cells, among them, alignates are nowadays the most studied and characterized for cell encapsulation technology

Alignates are linear unbranched polymers containing linked D-mamuronic acid (M) and L-guloronic acid (G)

Alignates create 3D structures when they react with multivalent ions. Divalent cations such as calcium bind between adjacent alignate chains (G-blocks) creating interchain bridges which cause gelling of the aqueous alignate solution

● U-capsules can be formulated by many different methods, the most often described system is based on an alignate core surrounded by a polycation layer which at the same time is covered by an outer alignate membrane. (the polycation forms a semipermeable membrane, which improbes the stability and biocompatibility of the u-capsule.)

● Different polycation suc as, poly-l-lysine (PLL), poly-l-ornithine (PLO), chitosan, among others have been employed to cover the alignate matrix

● Although capsules with alternatives materials have been developed, in vitro studies have not proven to be better and few in vivo data are available.

Table 1. Cell encapsulation approaches based on alignate matrices.

Requirements of the technologyOptimization process to

Come closer to a realisticProposal for clinical app.

Biocompatibility Optimal deliverysite Other issues

Monitor and remove All its contaminant

(endotoxins, certainProteins )

CommerciallyUltrapure aligates haveBeen found to contain

Residual proteins(J.Dusseault et al, 2006

S.K.Tom et al, 2006G.Orive et al, 2006)

Loss of 2-10% of capsuleDue to macrophages

Immune responseAgainst capsules Implanted IP was

More severe than SCAnd KC cases

Monitor theImplanted device

Alignate-basedRadiopaque

-Barium sulfate

-Orbismuth sulfate

Cell viability and capsulePermeability were not affectedBut the metals employed are

Toxic both for the encapsulatedCells and the recipient

X-ray monitoring(B.P.Barnett et al

2006)

The versatility of cell encapsulation

● Many disease are closely tied with deficient or subnormal metabolic and secretory cell functions (Parkinson disease, Diabetes mellitus, hepatic failure)

● It is often extremely complicated or even impossible to mimic the ”moment-to-moment” precise regulation and the complex role of the hormone, factor, or enzyme that is not produced by the body.

● A suitable election of the cells holds the key to the succes of any biomedical application :

– Bioorgans: primary cells ( i.e, hepatic islet)

– Living drug factories: genetically modified cells

– Stem cell technology

Concluding remarks

● With continuing advances in genetics, materials science, pharmaceutical technology, biology and chemical engineering, improvements will lead to progression in this therapeutic approach which may become one day closer to a realistic proposal for clinical application.

● Due to the major advantages that cell encapsulation offers as a living drug delivery system, it can be expected that its practical importance will continue to steadily increase in the future.