Therapeutic Protein Release from Degradable Layer-by-Layer Assembled Films for Sustained, Local Drug Delivery

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Depicts chemical structures of certain polymers used in accordance with the invention. Shown are the structures for polymer 1 (Poly1), heparin sulfate, chondroitin sulfate, and polymer 2 (Poly2). Note that Poly1 and Poly2 differ only by two methylene units in the backbone.Illustrates a scheme that may be used to construct a film using a cationic polymer (Poly1) comprising a cationic protein (lysozyme). Layers of a biological polyanion are deposited between layers of Poly1 and layers of lysozyme onto a substrate such as a slide. Thus, the film is comprised of tetralayers, each tetralayer having the structure (Poly1/polyanion/lysozyme/polyanion.)Shows results indicating that release is affected by temperature of release and the number of tetralayers. Time in days is plotted against total amount of protein released in μg. (A): Replicate samples dipped with the architecture [(Poly1/heparin/lysozyme/heparin)80] were released at room temperature and displayed a linear release curve. (B): Films with the architecture [(Poly1/heparin/lysozyme/heparin)50] were released at 37° C. and displayed a continued linear release profile. (C): Films comprised of various numbers of tetralayers were released in PBS. Both the amount of protein incorporated and the time to total release are increased with increasing numbers of tetralayers.Release curves of chondroitin-containing and heparin-containing films.
Mara Macdonald
Department of Health Sciences and Technology, MIT
Professor Paula Hammond
Department of Chemical Engineering, MIT
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Jon Gilbert
MIT Technology Licensing Officer
Patent Protection

Self Assembled Films for Protein and Drug Delivery Applications

US Patent 9,393,217
Release of a Model Protein from Biodegradable Self-Assembled Films for Surface Delivery Applications
Journal of Controlled Release, Nov 12, 2008, p. 228-234


Degradable layer-by-layer assembled films may be used to release therapeutic proteins, drugs, and other biologically relevant material in a sustained and local manner. These devices may function as patient implants, environmental modulators in tissue culture or other biological models, and in general as chemical dispensers.

Problems Addressed

Traditionally, localized polymer-based protein drug delivery methods have relied on the diffusion of encapsulated proteins through porous polymer membranes. While this approach has had some success, there are several disadvantages upon which may be improved. First, the chemical treatments these porous polymer membranes must undergo can degrade the fragile polypeptide drugs they encapsulate. Furthermore, the rate of diffusion of the drug depends on the difference between the drug's intramembrane and environmental concentrations. As a result, the rate of drug release exhibits a "burst release profile" in which the release rate is high in the beginning and wanes as time passes. A new protein drug encapsulation method that preserves the functionality of the protein drug and demonstrates a sustained, linear drug release profile would be a great improvement in the field of localized therapeutic protein drug delivery.


This invention incorporates layer-by-layer deposition technology in a novel method for a more gentle and controlled approach to localized drug release. Therapeutic drugs are incorporated by mild aqueous conditions into layers of oppositely charged polymers attached to a charged surface. The drugs are released through gradual ester degradation of the polymers in the membrane film. Thus far, pilot studies show that the incubation of films containing fifty tetralayers of Poly (beta-amino ester) and the protein drug lysozyme in PBS at 37 °C have yielded a linear, controlled release of lysozyme lasting five days. The lysozyme released retained 80-100% functionality, underscoring the mild processing conditions used to produce the films. Furthermore, these films were shown to be capable of being modified to contain both lysozyme and heparin, which lowers the chance of coagulation upon the film's surgical implantation. In the future, the drug release rate may be further controlled by adjusting the number of tetralayers or the polymer structure. In addition, other materials such as growth factors or cell matrix constructs may be incorporated into the tetralayers to tailor the film to specific applications.


  • Biocompatible with anticoagulant properties
  • Linear localized drug release profile in physiological conditions
  • Retention of protein drug potency after processing steps
  • Release rate, release duration, and film contents easily adjusted to match specific applications