Growth Factors Engineered for Super-Affinity to the Extracellular Matrix Enhance Tissue Healing

Toward Successful Tissue Repair The therapeutic use of growth factors in tissue regeneration has suffered from safety and efficacy issues. Reasoning that the unmet potential may be because of nonphysiological delivery, Martino et al. (p. 885) engineered growth factors to bind strongly to extracellular matrix proteins. These variants were able to induce superior tissue repair, compared to the wild-type proteins. Furthermore, unwanted side effects were decreased: For example, the engineered angiogenic growth factor VEGF showed reduced vascular permeability, a concern that has limited the therapeutic efficacy of wild-type VEGF. A strategy to engineer tissues uses substantially lower growth factor levels without compromising tissue viability. Growth factors (GFs) are critical in tissue repair, but their translation to clinical use has been modest. Physiologically, GF interactions with extracellular matrix (ECM) components facilitate localized and spatially regulated signaling; therefore, we reasoned that the lack of ECM binding in their clinically used forms could underlie the limited translation. We discovered that a domain in placenta growth factor-2 (PlGF-2123-144) binds exceptionally strongly and promiscuously to ECM proteins. By fusing this domain to the GFs vascular endothelial growth factor–A, platelet-derived growth factor–BB, and bone morphogenetic protein–2, we generated engineered GF variants with super-affinity to the ECM. These ECM super-affinity GFs induced repair in rodent models of chronic wounds and bone defects that was greatly enhanced as compared to treatment with the wild-type GFs, demonstrating that this approach may be useful in several regenerative medicine applications.