Loss of periodontal ligament tissue (PDL) and attachment is a serious complication of periodontal diseases - the most prevalent dental health problems. PDL-degeneration leads to alveolar bone degeneration, infection, gingivitis, and eventual tooth loss. There is currently no product that can cure PDL-degeneration as regeneration requires the combinatorial process of regenerating cementum, signaling the existing relevant cells to proliferate and form PDL, and its integration into a functional system. Current restorative treatments utilize cell-based tissue regeneration, synthetic scaffolds, tissue grafts with limited, temporary success. A market product, e.g., claims to restore periodontium using harvested fetal swine periodontal tissue with highly variable clinical outcomes. Although these traditional procedures are well-established and show some success, their efficacy is limited due to the lack of structural and functional integration of a deposited layer with the underlying tooth, specifically integration into the remineralized cementomimetic layer. GEMSEC labs have developed a proprietary technology dubbed “peptide-guided remineralization” which facilitates new mineral formation using protein-derived peptides and have successfully restored dental hard tissues via several case studies including enamel, cementum, dentin under in-vitro and in-vivo conditions. Translating this technology into a daily-use product, we propose a PDL-regenerating chimeric construct which includes a biomineralizing peptide, ADP5, derived from the key enamel protein, amelogenin, with cell signaling moieties. Herein, we aim to use established bioinformatics, machine-learning tools, and high-throughput experimentation to identify peptides from proteins involved in PDL development cell-signaling towards controlled biomineralization, bioadhesion, and cell-signaling functionalities necessary for PDL regeneration. Addressing current treatment protocol limitations, the interdisciplinary approaches developed in this project are designed for the regeneration and formation of fully functional PDL. 

Children with cerebral palsy (CP) exhibit slower walking speeds and elevated energetic costs of walking compared to typically-developing children, limiting their ability to engage with peers. To increase walking speed and reduce the energetic demands of walking, children with CP are often prescribed ankle-foot orthoses (AFOs). However, changes in walking speed, step length, and the energy costs with AFOs compared to barefoot walking in children with CP are highly heterogeneous, limiting the potential efficacy of AFO prescription. The primary neurological impairment in CP: impaired motor control, is a potential contributor to heterogeneous response to AFOs. We are investigating how increased severity of impaired motor control impacts changes in speed, step length, and energy during walking in response to varying AFO flexion stiffness. We hypothesize that increasing motor impairment severity will correspond to increased sensitivity of walking energy, speed, and step length to AFO stiffness. We developed a musculoskeletal simulation framework used to simulate walking with AFOs of varying stiffness and for different levels of impairments severity. For each simulation, we will estimate the sensitivity of walking energy, step length, and walking speed to AFO stiffness. Preliminary results showed that walking energy with more severely-impaired control was more sensitive to AFO stiffness than unimpaired control. We have since expanded the framework’s capabilities to adopt different speeds and step lengths. We have shown that the framework is robust to uncertainty in initialization parameters: the coefficient of variation of simulated walking energy was 0.11, which is reasonable for human gait. Identifying the relationship between impairment severity and sensitivity to AFO stiffness may highlight the relative importance of precise AFO tuning to achieve positive gait outcomes in children with CP. This work provides an early step towards using motor control to inform clinical AFO prescription.

Nanofibers have broad capabilities in biomedicine, e.g. drug delivery and tissue engineering, because of their diverse tunable properties. For these purposes, nanofibers often must be patterned to be integrated in devices or to optimize their function. Current nanofiber patterning methods lack user-control over design or alter fiber integrity. To optimize and expand the applications of nanofibers, there is a need for a versatile nanofiber patterning strategy that maintains material integrity and function and can be generalized for patterns of different complexity and dimensions. This project aims to address this need with an in situ patterning strategy that allows for complex, three-dimensional patterning at the milli/microscale with different fiber materials. The approach consists of a two-layer composite electrospinning collector with an insulative layer and conductive recessed patterns. An inexpensive collector fabrication method was designed for rapid prototyping. Collector design features predicted to affect fiber deposition were evaluated by quantifying fiber selectivity. Optimal formulations of nanofiber materials were experimentally evaluated based on reproducibility, fiber yield, and selectivity to delineate key polymer solution properties affecting patterning. This project offers a guiding foundation to adapt this patterning strategy to various applications of nanofibers by tuning fiber formulations and specific collector design features.

Implanted biomedical devices are becoming increasingly common for the treatment of tissue defects and organ failures. However, there is an ongoing issue of biocompatibility, where the host body constantly attempts to degrade the foreign object while it can’t most of the time, especially in the case of synthetic polymers. Consequently, virtually all implants will undergo an immune response named foreign body reaction and eventually get encapsulated in collagen, which can be detrimental to the device’s designated function, especially for drug delivery systems. Extensive research attempting to improve biomaterial integration has been conducted in the past decades. Recent studies suggested that the in vivo vascularization within and around a porous polymeric biomaterial is partially driven by the local phenotypic expression of macrophages, where the M1 macrophage was specifically shown to play an angiogenic role. It was also observed that the in vitro pre-vascularization of biologically-derived constructs accelerates and enhances tissue vascularization in vivo. Enlightened by these findings, I proposed to modulate both macrophage phenotypes at the material-tissue interface and scaffold pre-vascularization to restore tissue homeostasis. Two tools previously developed by my mentor’s research groups are vital for my study: the engineered M1-inducible macrophages (i-M1macs) and sphere-templated porous poly(HEMA) biomaterial scaffolds. Three main aims were constructed, where the first two aims are to optimize in vitro the scaffold pre-vascularization from endothelial cells and activation of i-M1macs in scaffolds respectively. The third aim is to determine the effect of macrophage modulation and scaffold pre-vascularization on the foreign body response to biomaterials in vivo. Findings from my research are expected to improve our understanding of the correlation of macrophage plasticity, material porosity, scaffold pre-vasculature, and tissue vascularization, which can be crucial for the development of a novel cell therapy that improves biomaterial integration and ultimately, the quality of life of people with biomedical implants.