Polysaccharide putty formulations for tissue regeneration

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Project Summary/Abstract The broad, long-term objectives of this proposal are to enhance the utility of cellulose-based biomaterials for tissue repair by developing and evaluating a new and innovative composite that address current limitations. Bacterial cellulose hydrogels and extracellular matrices have shown excellent regeneration capabilities in multiple tissue types. However, these materials lack mechanical strength and degradation features needed for specific applications such as bone repair, and have limited options for storage, handling, and sterilization. Plant- derived cellulose in its derivative cellulose acetate (CA) form is capable of creating mechanically competent porous scaffolds that are effective in bone regeneration. However, premade CA scaffolds with defined sizes, shapes, and pore properties present challenges in adapting to complex bone defects. Additionally, the relatively slow degradation rate of cellulose/CA can limit its ability to control factor release and heal bone. Combining CA with CA phthalate (CAP) and nanoclay (NC) has the potential to address some of these weaknesses. This cellulose-based composite forms a putty that can be molded into complex shapes and becomes strong as it hardens, making it adaptable to diverse bone defects. Under physiologic conditions, CAP erodes before the slower-degrading CA matrix, enabling a dynamic system that generates interconnected pores and tunable growth factor release profiles and degradation. A CA/CAP/NC composite allows flexible incorporation of multiple bioactive factors for varied effects: within CA for early, sustained release; within CAP for pulsed release; and/or into NC embedded within the CA/CAP for delayed, sustained release. This also allows factors to be released in parallel and/or sequentially. Detailed, long-term in vitro and in vivo characterizations of this cellulose biomaterial, including its ability to balance strength and porosity and the effects of osteoclasts on its degradation, remain knowledge gaps for advancing this transformative and natural biomaterial platform. Based on current knowledge, it is hypothesized that this dynamic cellulose-based putty will impart composition-dependent changes of strength and erosion in 3D microenvironments leading to varied bioactive factor release rates, vasculature development, and tissue ingrowth during bone repair. This will be tested in four Specific Aims: Aim 1: Characterize physicochemical and release properties of novel cellulose derivatives and compositions in vitro. Aim 2: Evaluate biocompatibility and bioactivity of released molecules in an in vivo subcutaneous implantation model. Aim 3: Evaluate cellular effects of putty formulations with early to long-term release profiles on a cranial flat-bone healing defect. Aim 4: Assess putty formulations with early to long-term release profiles on bone healing at a load- bearing site in a critical-sized long-bone defect in rabbit ulna. These studies will address several knowledge gaps for using cellulose biomaterials in bone healing. If this enabling putty technology is successful, it may be transformative to the field and adapted for other repair challenges in bone as well as a coating for biomedical implants.