Bifunctional, pH-responsive zeolite-bisphosphonates complex as a base for the production of smart bone implant for osteoporotic fracture treatment

OPUS 22

Funding Organization: National Science Centre

Leader: Medical University of Lublin

Partner: Lublin University of Technology

Project title: Bifunctional, pH-responsive zeolite-bisphosphonates complex as a base for the production of smart bone implant for osteoporotic fracture treatment

Agreement number: UMO-2021/43/B/NZ7/00447

Project implementation period: 02.11.2022 r. – 01.11.2026 r.

Principal Investigator (Medical University of Lublin): prof. dr hab. Agata Przekora-Kuśmierz

Principal Co-investigator  (Lublin University of Technology): prof. dr hab. inż. Wojciech Franus

Project value: 3 351 950,00 PLN

Funds granted for Medical University of Lublin : 2 308 850,00 PLN

Funds granted for Lublin University of Technology: 1 043 100,00 PLN

Abstract: Osteoporosis is a metabolic skeletal disease characterized by microarchitectural deterioration and decreased bone mass, that triggers a loss of bone strength and raised fracture risk. It develops slowly over several years and is a multifactorial disease caused by endocrine disorders, genetic mutations, and nutritional deficiency. Bone is a dynamic tissue that undergoes remodeling in which damaged or old bone is removed by osteoclasts (bone-resorbing cells) and
replaced with a new tissue by osteoblasts (bone-forming cells). Disturbance of balance between osteoclastic bone resorption and osteoblastic bone formation results in the development of osteoporosis. Therapies aiming to inhibit osteoclast formation and bone resorption are the foundation for osteoporosis treatment. Commonly used anti-bone resorption drugs include bisphosphonates, calcitonin, raloxifene, estrogen, denosumab. The bisphosphonates, such as alendronate, risedronate sodium, zoledronic acid, are the most widely used drugs which can successfully reduce bone
destruction. In clinical use, bisphosphonates are mainly administrated orally. Nevertheless, long-term clinical use of bisphosphonates during pharmacological therapy is associated with serious complications including gastrointestinal reactions, hypocalcemia, and kidney failure.
The aim of this project is to develop pH-responsive zeolite-bisphosphonates complex that would be used as a base for the production of smart bone implant for osteoporotic fracture treatment applications. To enhance bone formation process, Ca2+ and Mg2+ ions will be introduced to the zeolites structure through ion-exchange process (Na+ ions exchanged to Ca2+ and Mg2+ ions). Mentioned ions are known to support osteoblast adhesion and their bone-forming
activity. Bisphosphonates will be incorporated to the zeolites structure using chitosan molecules as a linker. After implantation, developed smart biomaterials would be exposed to an acidic pH (~4.0-4.5) which occurs during osteoclast-mediated bone resorption. In turn, acidic pH would initiate the release of bisphosphonates into the bone environment (due to the dissolution of chitosan linker), inhibiting osteoclasts. It would cause a significant increase in local drugconcentration compared to its oral administration. Moreover, proposed approach would protect patients from side effects of oral drug therapy. Importantly, the developed pH-responsive zeolite-bisphosphonates complex-based bone implant would simultaneously support bone regeneration and decrease bone resorption by osteoclasts at the implantation site. The project plan is also to comprehensively assess biomedical potential of produced novel bone implants via determination of their mechanical properties (compressive strength, Young’s modulus), porosity, specific surface area (SSA), microstructure, roughness, wettability, biodegradation, bioactivity (biomineralization in vitro), liquid uptake ability, release profile of bisphosphonates, and biological properties (cytotoxicity, cell adhesion, morphology and proliferation, osteogenic differentiation, osteoblast metabolism, osteoclast apoptosis, and inflammatory response). Importantly, osseointegration process will be reliably determined using ex vivo human bone explant model – an innovative method for biomaterial testing developed by our research team.