One-Step Preparation of an Injectable Hydrogel Scaffold System Capable of Sequential Dual-Growth Factor Release to Maximize Bone Regeneration

Abstract

Numerous growth factors are involved in the natural bone healing process, which is precisely controlled in a time- and concentration-dependent manner. Mimicking the secretion pattern of growth factors could be an effective means to maximize the bone regeneration effect. However, achieving the sequential delivery of various growth factors without the use of multiple materials or complex scaffold designs is challenging. Herein, an injectable poly(organophosphazene) hydrogel scaffold (IPS) encapsulating bone morphogenetic protein (BMP)-2 and TGF beta-1 (IPS_BT) is studied to mimic the sequential secretion of growth factors involved in natural bone healing. The IPS_BT system is designed to release TGF beta-1 slowly while retaining BMP-2 for a longer period of time. When IPS_BT is injected in vivo, the hydrogel is replaced by bone tissue. In addition, angiogenic (CD31 and alpha-smooth muscle actin (alpha-SMA)) and stemness (Nanog and SOX2) markers are highly upregulated in the early stages of bone regeneration. The IPS system developed here has promising applications in tissue engineering because 1) various amounts of the growth factors can be loaded in one step, 2) the release pattern of each growth factor can be controlled via differences in their molecular interactions, and 3) the injected IPS can be degraded and replaced with regenerated bone tissue.