Tissue integration of growth factor-eluting layer-by-layer polyelectrolyte multilayer coated implants

Abstract

Drug eluting coatings that can direct the host tissue response to implanted medical devices have the potential to ameliorate both the medical and financial burden of complications from implantation. However, because many drugs useful in this arena are biologic in nature, a paucity of delivery strategies for biologics, including growth factors, currently limits the control that can be exerted on the implantation environment. Layer-by-Layer (LbL) polyelectrolyte multilayer films are highly attractive as ultrathin biologic reservoirs, due to conformal coating of difficult geometries, aqueous processing likely to preserve fragile protein function, and tenability of incorporation and release profiles. Herein, we describe the first LbL films capable of microgram-scale release of the biologic Bone Morphogenetic Protein 2 (BMP-2), which is capable of directing the host tissue response to create bone from native progenitor cells. Ten micrograms of BMP-2 are released over a period of two weeks in vitro; less than 1% is released in the first 3 hours (compared with commercial collagen matrices which can release up to 60% of BMP-2, too quickly to induce differentiation). BMP-2 released from LbL films retains its ability to induce bone differentiation in MC3T3 E1S4 preosteoblasts, as measured by induction of alkaline phosphatase and stains for calcium (via Alizarin Red) and calcium matrix (via Von Kossa). In vivo, BMP-2 film coated scaffolds were compared with film coated scaffolds lacking BMP-2. BMP-2 coatings implanted intramuscularly were able to initiate host progenitor cells to differentiate into bone, which matured and expanded from four to nine weeks as measured by MicroCT and histology. Such LbL films represent new steps towards controlling and tuning host response to implanted medical devices, which may ultimately increase the success of implanted devices, provide alternative new approaches toward bone wound healing, and lay the foundation for development of a multi-therapeutic release coating.

Nanostructured Injectable Cell Microcarriers for Tissue Regeneration

“…A primary advantage of the LbL self-assembly technique is the generation of ordered structure at nanometer thickness (with an achievable resolution of 1 nm) on substrates of various shapes and sizes [139]. The drug load can be easily tuned with the number of layers incorporated [140]. The LbL technique has been used to encapsulate drugs onto microsphere substrates [141][142][143].…”

Temperature-induced molecular transport through polymer multilayers coated with PNIPAM microgels

“…Nowadays these multilayer films are extensively used as reservoirs to host bioactive molecules aiming at biological applications. [6][7][8][9][10] A variety of molecules can be embedded into the films; they include small drugs and dyes, [11][12][13][14][15][16][17] proteins and peptides, [18][19][20][21] or nucleic acids. 22,23 Extensive reviews on the reservoir properties of the multilayers can be found elsewhere.…”

“…10,30 The multilayers can release biomolecules reaching the cells thereby inducing cellular response such as adhesion, migration or differentiation. 21,34,35 However, to stimulate a cellular response, it is necessary to ensure the delivery of biomolecules from the film to the cells. To date, stimuli-responsive multilayers have been prepared by employing polymers sensitive to pH, ionic strength, and temperature variation.…”

In-situ monitoring of drug release from therapeutic eluting polyelectrolyte multilayers under static and dynamic conditions

“…The test tube is then immersed in the water bath for temperature control. The drug being released is measured by sampling the releasing medium at sequential time intervals and subjected to drug test using a variety of methods such as standard ELISA [16], radio-labels [17], or UV-Vis absorbance [18]. This static method, though helping to produce a large amount of information on the drug release profiles, does not take into consideration of the physiologically relevant conditions.…”