Sunday, May 18, 2025
5/18/2025
ABC Hydrogel for the treatment of osteonecrosis - Project Summary/Abstract Osteonecrosis (ON) is one of the most debilitating bone diseases, with approximately 20,000-30,000 new cases diagnosed annually in the US and over 20 million worldwide. The disease progresses in 80% of patients, leading to bone collapse and osteoarthritis. Current ON treatments remain suboptimal. Non-operative treatments fail to reverse ON progression due to insufficient local bioavailability caused by poor circulation in ON-affected bone. Operative treatments aim to “Demolish and Rebuild” by removing as much necrotic bone as possible and filling the large bone void with bone substitutes, which does not improve the prognosis and raises concerns of iatrogenic bone collapse, heterotopic ossification, and pulmonary embolism. Due to treatment failures, ON patients often require total joint replacement, which is not ideal in young adults given their high physical demand and longevity. To solve the challenge, we propose to develop a novel pro-Angiogenic Bone Coating hydrogel (ABC hydrogel), which is a copolymer of gelatin and hyaluronic acid, which can provide high coupling and adjustable degrees of bisphosphonate (polyBP) and pro-angiogenic QK peptide (polyQK, VEGF mimicking peptide). Our preliminary studies found: 1) Injecting ABC hydrogel via small intraosseous needles produced a broad distribution within the necrotic bone without leakage; 2) After injection, ABC hydrogel can quickly transition to liquid at body temperature without blocking the marrow space, which is critical for angiogenesis, new repair tissue ingrowth, and avoiding pulmonary embolism; 3) The bifunctional ABC molecule can attach to the necrotic bone surface via polyBP component to inhibit the osteoclast activity and accelerate revascularization via polyQK component; 4) Although there is concern about delayed bone remodeling related to the bisphosphonate (BP) component, our preliminary results found that the ABC hydrogel treatment in ON rats effectively prevented bone deformity and allowed bone remodeling. These promising characteristics make the ABC hydrogel an excellent candidate for treating ON. This study proposes three specific aims: Aim 1 is to determine the physical, chemical, and cytocompatibility of the ABC hydrogel for ON treatment. This includes characterizations of the chemical structure and sol-gel transition, tests of the injection pressure and hydrogel distribution, and assessments of the degradation and cytotoxicity. Aim 2 is to optimize the pro-angiogenic capability of the ABC hydrogel. ABC hydrogel formulations with different QK and BP components will be studied, including evaluations of in vitro angiogenic bioactivities, ex vivo release of pro-angiogenic QK, and in vivo revascularization. Aim 3 is to optimize the antiresorption capability of ABC hydrogel to prevent early bone resorption while allowing restoration of bone remolding. ABC hydrogel formulations with maximum QK components and different BP components will be studied, including evaluations of in vitro anti-resorption properties, in vivo BP release, and in vivo ON therapeutic effects. Successful completion of this project will develop a novel bioactive hydrogel system, establish a promising cell-free strategy, and open a new direction of using a minimally invasive manner for ON treatment.
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