Biomaterials as carriers for bone active molecules-An approach to create off-the-shelf bone substitutes

Sammanfattning: Bone tissue is commonly transplanted during orthopedic surgeries, primarily for the management of bone defects caused by trauma or various orthopedic conditions including, but not limited to, infections and tumours. Bone grafts are a surgeon’s choice, but their associated drawbacks are paving the way for biomaterial based bone graft substitutes. Biomaterials inherently lack the ability to induce significant amount of bone growth due to which they may be combined with cells, biomaterials, growth factors and drugs to regenerate functional bone tissue. This thesis focused on characterizing biomaterial carriers that can locally deliver bone active molecules for bone regeneration and potentially act as an alternative to conventional bone grafting. We focused on the delivery of recombinant human bone morphogenic protein-2 (rhBMP-2) as a bone inducing anabolic growth factor. Simultaneously, we have used an osteoclast inhibiting bisphosphonate, zoledronic acid (ZA) to prevent BMP-2 induced premature bone resorption. Three different biomaterials scaffolds; a microporous calcium sulphate (CaS)/hydroxyapatite (HA), a macroporous gelatin-CaS/HA and a collagen membrane were used in distinct animal models of bone regeneration.The carrier properties of the three biomaterials in the ectopic muscle pouch model (studies 1, 4 and 5) showed that the tested materials were efficient carriers of rhBMP-2 and ZA and that co-delivery of rhBMP-2 and ZA regenerated higher volume of bone compared to rhBMP-2 alone. Studies 2& 3 show that the CaS/HA material locally delivering ZA or ZA+rhBMP-2 could be efficiently used for bone regeneration in clinically relevant bone defect models. These studies also indicated that local delivery of ZA not only has an anti-osteoclast effect but it also has an anabolic role. Study 4 compared the developed porous biomaterial with the current FDA approved collagen sponge and results indicated that the developed biomaterial outperforms the current marketed product for the delivery of rhBMP-2. During this study, it was also established that co-delivery of rhBMP-2 with ZA could reduce the effective rhBMP-2 doses by up to four times, which is crucial to reinstate BMPs into the clinics. Study 5 was a follow-up of study 2 separating the metaphyseal defect healing in two stages; 1) Healing the cancellous bone using a porous material and 2) Guiding cortical regeneration using a thin collagen membrane. Significantly better cortical healing was noted using this approach in comparison to study 2.In summary, this work describes promising strategies for bone regeneration. It established how the release of bone active molecules can be controlled by the choice of carrier material and how we can decrease the minimally effective dose of rhBMP- 2 by up to four times. These findings can potentially be translated from the bench to the bedside. The materials and methods developed within the scope of this work can be used in a variety of orthopedic conditions and can provide the surgeon with an effective off-the-shelf substitute for bone replacement, in turn leading to improved care of the patient.