Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

Abstract

Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration.regenerative medicine | layer-by-layer | biomaterial | controlled drug release | wound healing

Sustained dual release of placental growth factor-2 and bone morphogenic protein-2 from heparin-based nanocomplexes for direct osteogenesis

“…[1][2][3] Its challenging nature is in part due to the development of bone tissue being a complex and coordinated process, involving direct and indirect osteogenesis. Indirect osteogenesis is mainly mediated by angiogenesis, which provides oxygen, nutrients, and pro-osteogenic cells to facilitate bone regeneration.…”

“…6 There has been increasing interest in mimicking the endogenous bone regeneration cascade by utilizing exogenous GFs, which play key roles in direct and indirect bone healing. 2 Among the various direct osteogenic GFs, bone morphogenic protein-2 (BMP-2) is believed to be the most potent and has received clinical clearance from the US Food and Drug Administration. [7][8][9] However, a large dose of BMP-2 is necessary for an effective therapeutic effect because BMP-2 stimulates osteoregeneration only at a high concentration, 10,11 and its half-life is as short as 7 minutes in vivo.…”

“…38,39,43 Also, Martino et al 40 showed that domain II (Fg β15-66 (2) ) of heparin exhibits high affinity for GFs in general, but with heparin displaying a fourfold stronger affinity for PlGF-2 than for BMP-2; 44 they also revealed a specific heparin-binding portion of PlGF-2 spanning residues 123-144 and having the sequence RRPKGRGKRRREKQRPTDCHL. 44 However, in our study, the difference of loading efficiency between PlGF-2 and BMP-2 was not so prominent, perhaps because both GFs were applied at overall low doses and exhibited high affinity to heparin.…”

B 12 -dependent photoresponsive protein hydrogels for controlled stem cell/protein release

“…Protein drugs, an important category of modern therapeutics, have a short half-life time inside the body because of rapid plasma clearance and proteolytic degradation, which constitutes a fundamental challenge for their delivery (42,43). The ELP fusion strategy has previously been shown to be able to significantly enhance pharmacokinetics and efficacy of a protein drug by prolonging its circulating half-life (44).…”

Growth factor-eluting technologies for bone tissue engineering

“…For example, 3D printed β-tricalcium phosphate/ polycaprolactone scaffolds coated with LbL films consisting of a poly (β-aminoester) (Bpoly 2^), chondroitin sulphate (CS), and BMP-2 resulted in a system that successfully induced in vivo bone formation when implanted intramuscularly in rats [76]. Meanwhile, Hammond et al developed LbL nanolayer coatings of BMP-2 and PDGF on PLGA membranes and found that low-dose dual delivery resulted in better outcomes (healing rate, bone volume, mechanical properties, and histology) in a rat calvaria defect model than BMP-2 delivery alone (at both 200 ng and 2 μg doses of BMP-2) [101].…”