Chondroitin Sulfate Glycosaminoglycan Scaffolds for Cell and Recombinant Protein-Based Bone Regeneration

Abstract

Bone morphogenetic protein 2 (BMP‐2)‐loaded collagen sponges remain the clinical standard for treatment of large bone defects when there is insufficient autograft, despite associated complications. Recent efforts to negate comorbidities have included biomaterials and gene therapy approaches to extend the duration of BMP‐2 release and activity. In this study, we compared the collagen sponge clinical standard to chondroitin sulfate glycosaminoglycan (CS‐GAG) scaffolds as a delivery vehicle for recombinant human BMP‐2 (rhBMP‐2) and rhBMP‐2 expression via human BMP‐2 gene inserted into mesenchymal stem cells (BMP‐2 MSC). We demonstrated extended release of rhBMP‐2 from CS‐GAG scaffolds compared to their collagen sponge counterparts, and further extended release from CS‐GAG gels seeded with BMP‐2 MSC. When used to treat a challenging critically sized femoral defect model in rats, both rhBMP‐2 and BMP‐2 MSC in CS‐GAG induced comparable bone formation to the rhBMP‐2 in collagen sponge, as measured by bone volume, strength, and stiffness. We conclude that CS‐GAG scaffolds are a promising delivery vehicle for controlling the release of rhBMP‐2 and to mediate the repair of critically sized segmental bone defects. stem cells translational medicine 2019;8:575–585

Glycosaminoglycan-based biomaterials for growth factor and cytokine delivery: Making the right choices

“…CS has been used for sustained delivery of BMPs in the form of coatings [114] and scaffolds [74–76]. A CS-based scaffold was compared to collagen sponges (the standard clinical delivery method) as BMP-2 delivery systems.…”

“…A CS-based scaffold was compared to collagen sponges (the standard clinical delivery method) as BMP-2 delivery systems. In vitro extended release of 7 μg of BMP-2 over 16 days was observed in the CS scaffold but not the collagen sponge, stimulating bone formation in a critically sized femoral defect in rats [74]. CS-collagen scaffolds were coated with poly-L-lactide (PLLA) and sucrose acetate isobutyrate to extend the release of BMP-2, resulting a release of 50% of growth factor over 15 days.…”

“…GAGs can be physically fabricated into different forms with varied mechanical properties, or alternatively can be present as a minor component within a bulk scaffold that provides desirable mechanical and structural properties. GAG-based biomaterials have been developed in a variety of physical forms for different applications, including hydrogels [24,40–58], surface coatings [59–61], nano- [62–64] and micro-particles [65–68], coacervates [69–73], and fibrous scaffolds [74–78] (Table 1). In many cases, chemical modification of GAGs assists synthesis or allows the addition of new properties of materials ( e.g.…”

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“…To improve the clinical potential of this strategy and move toward the development of an injectable biologic therapy for large bone defect healing in humans, Andrews et al next evaluated bone regeneration using a chondroitin sulfate glycosaminoglycan scaffold for the delivery vehicle for recombinant human (rh) BMP‐2 and BMP‐2 overexpressing MSCs. Writing in STEM CELLS Translational Medicine , the authors initially discovered extended BMP‐2 release from the chondroitin sulfate glycosaminoglycan (GAG) scaffold when compared with a collagen sponge (Col), the currently used clinical gold standard for bone regeneration. The administration of this newly developed strategy within electrospun polycaprolactone nanofiber meshes to increase retention within the defect and enhance BMP‐2 delivery permitted comparable bone formation in critically sized femoral defects in model rats as measured by bone volume, strength, and stiffness when again compared with the collagen sponge.…”

“…In our second Featured Article published this month in STEM CELLS , Zhou et al describe a synergistic interaction between Krüppel‐like factor 2 (KLF2)‐expressing human (h)MSCs and endothelial cells that may significantly influence future bone regeneration and vascular network bioengineering strategies . In a Related Article recently published in STEM CELLS Translational Medicine , Andrews et al compared bone repair techniques and demonstrated the utility of a bone morphogenetic protein 2 (BMP‐2)‐releasing chondroitin sulfate glycosaminoglycan scaffold as a means to support large bone defect healing by engineered MSCs …”