Controlled Release from Porous Platforms

The authors present a method for controlling the release of therapeutics by applying a plasma polymer layer to the surface of porous materials.
Aug 01, 2011

Advances in nanoscience and nanotechnology have led to the development of novel drug-delivery platforms. During the past decade, attention has focused on nanoporous materials of which the pore size, pore distribution, geometry, and surface functionality can be controlled at the micro- and nanoscale (1–4). For example, porous alumina and porous titanium architectures obtained electrochemically have been proposed for implantable medical devices such as bone implants, vascular stents, and immunoisolation capsules (5–11). The interest in porous materials for therapeutic implants arises not only because of their ability to support tissue integration, but also because they can carry drugs (4, 6). The pores of these materials can be loaded with therapeutic agents and thus act as reservoirs for slow drug elution over extended periods of time, ranging from several days to several weeks (4, 6, 7). The advantages of local therapy through extended release time are high therapeutic concentrations at the target site and minimal systemic exposure (4, 7).

Porous aluminum has been used extensively as a scaffold for bone-tissue engineering applications. The biocompatibility of porous aluminum has been established, and the material has current clinical applications in orthopedic and dental implants (12). Also biocompatible, titanium and its alloys, particularly Ti-6Al-4V, have been used in orthopedic and dental implants extensively since the 1970s (13). It is estimated that more than 500,000 total joint replacements, primarily of hips and knees, and 100,000–300,000 dental implants are provided each year in the United States (13). About 25% of hip-replacement surgeries were undertaken to correct the failure of a previous implant. If an implant is improperly installed, loosening and osteolysis can occur. To overcome this problem, implant bone material should stimulate rapid bone regeneration to fill deficient bones and affix the implant firmly to the bone. The aim of the current research was to engineer bone implants that control and guide rapid healing (12, 13).

In 1994, two large trials demonstrated the superiority of coronary stents over conventional angioplasty in the treatment of coronary artery disease by showing 30% reductions of restenosis rates (14). However, such interventions are associated with major complications. For example, the proliferation of vascular smooth muscle cells (VSMC)can narrow the prosthesis, and endothelial-cell (EC) injury and dysfunction can result in thrombosis. A stent surface that incorporates titanium nanotubes can promote re-endothelialisation and decrease VSMC proliferation (8). Titanium nanotubes improve the proliferation and function of endothelial cells, decrease the proliferation of VSMCs, and enhance the production of prostaglandin I2, which mitigates thrombosis and restenosis (8).

To understand how endothelial cells interact with TiO2 nanostructured surfaces (i.e., how nanotopography affects the morphology of ECs), scientists grew bovine aortic endothelial cells on nanotubular and flat surfaces (8). Cells on nanotubular substrates had elongated morphologies, but cells on the flat surfaces were spread out and covered greater surface areas. Because of the elongation, cells on nanotubes covered 60% of the average area occupied by the control cells. The elongated cells also had increased proliferation and extracellular matrix production when compared with their spread-out counterparts. In addition, elongated cells had higher migration speeds. Since migration into the wound site is a major mode of re-endothelialization, enhanced EC motility may greatly improve healing after injury or device implantation (8).

The encapsulation of living cells (i.e., cellular immunoisolation using semipermeable porous aluminum barriers) has also been investigated in the past several decades as a potential treatment for diseases such as Parkinson's, Alzheimer's and Type I diabetes (11). The encapsulation of living cells is a promising future therapy because immunoprotected cells, such as pancreatic islets or hepatocytes, can respond physiologically both in vitro and in vivo to appropriate stimuli (11).

Scientists have adopted two general strategies to control drug release rate from porous materials. The first strategy relies on the adjustment of pore diameter and pore depth to control drug loading and release (4). The second uses surface functionalization of the pores, which affects drug affinity, and consequently release kinetics (4). However, these strategies have drawbacks. For example, in both strategies, the release kinetics are marked with an initial burst that may not be desirable in some applications. In addition, reducing the pore diameter to extend the length of drug release leads to a reduced pore volume and, consequently, less drug can be stored (6, 7). This article introduces a novel strategy for controlling the release of therapeutics from porous materials and demonstrates its applicability using model antibiotics and a protein.