Decorin-supplemented collagen hydrogels for the co-delivery of bone morphogenetic protein-2 and microvascular fragments to a composite bone-muscle injury model with impaired vascularization.

Abstract

Traumatic musculoskeletal injuries that result in bone defects or fractures often affect both bone and the surrounding soft tissue. Clinically, these types of multi-tissue injuries have increased rates of complications and long-term disability. Vascular integrity is a key clinical indicator of injury severity, and revascularization of the injury site is a critical early step of the bone healing process. Our lab has previously established a pre-clinical model of composite bone-muscle injury that exhibits impaired bone healing; however, the vascularization response in this model had not yet been investigated. Here, the early revascularization of a bone defect following composite injury is shown to be impaired, and subsequently the therapeutic potential of combined vascularization and osteoinduction was investigated to overcome the impaired regeneration in composite injuries. A decorin (DCN)-supplemented collagen hydrogel was developed as a biomaterial delivery vehicle for the co-delivery microvascular fragments (MVF), which are multicellular segments of mature vasculature, and bone morphogenetic protein-2 (BMP-2), a potent osteoinductive growth factor. We hypothesized that collagen + DCN would increase BMP-2 retention over collagen alone due to DCN's ability to sequester TGF-ß growth factors. We further hypothesized that MVF would increase both early vascularization and subsequent BMP-2-mediated bone regeneration. Contrary to our hypothesis, BMP + MVF decreased the number of blood vessels relative to BMP alone and had no effect on bone healing. However, collagen + DCN was demonstrated to be a BMP-2 delivery vehicle capable of achieving bridging in the challenging composite defect model that is comparable to that achieved with a well-established alginate-based delivery system. STATEMENT OF SIGNIFICANCE: We have previously established a model of musculoskeletal trauma that exhibits impaired bone healing. For the first time, this work shows that the early revascularization response is also significantly, albeit modestly, impaired. A decorin-supplemented collagen hydrogel was used for the first time in vivo as a delivery vehicle for both a cell-based vascular therapeutic, MVF, and an osteoinductive growth factor, BMP-2. While MVF did not improve vascular volume or bone healing, collagen + DCN is a BMP-2 delivery vehicle capable of achieving bridging in the challenging composite defect model. Based on its support of robust angiogenesis in vitro, collagen + DCN may be extended for future use with other vascular therapeutics such as pre-formed vascular networks.