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Tailoring Regenerative Therapies to Enhance Wound Healing Outcomes
Hodge, Jacob Gregory
Hodge, Jacob Gregory
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Abstract
Wound healing is a physiological regenerative process that consists of a dynamic series of interrelated events that are highly dependent on diverse paracrine signaling for proper progression through the phases of wound healing. However, many patients and wound types can be predisposed to inadequate progression through the phases of wound healing, subsequently resulting in atypical healing and/or protraction of the wound healing response. Notably, aberrant wound healing progression is associated with insufficient epidermal regeneration, a critical process of wound closure, and ultimate propagation of chronic wounds. The treatment of complex wounds affects millions of patients every year in the US, with chronic non-healing wounds associated with poor quality of life, adverse health outcomes, and a significant strain and burden to the healthcare system. Therefore, there remains a critical need to develop targeted therapies that can circumvent aberrant wound healing and promote the proper progression through the phases of wound healing.Therapeutic interventions for wounds encompass a diverse array of physical, mechanical, material, chemical and biological based modalities that have been shown to modulate the wound healing response in a variety of ways; however, many currently utilized therapies lack an effective targeted approach. Interestingly, tissue engineering and regenerative medicine approaches for wound care applications have grown significantly in the last several years. Recent investigations into Mesenchymal Stem Cells (MSCs) have demonstrated promise in augmenting the tissue regenerative response of wounds via their intrinsic multipotent nature and the compositional plasticity of their secretory profile. Additionally, priming of MSC populations has demonstrated the capacity to modulate and control cellular activity. Yet, current ex vivo culture technologies result in precipitous decline in the regenerative potential of MSCs and a decreased translatability of clinically viable and reproducible products. These changes are compounded by lack of standardized culture conditions, creating a bottleneck in the development of regenerative therapeutics. Thus, there is a critical need for developing culture systems for improved MSC expansion that allow significant expandability of cell numbers and their regenerative byproducts.Although a number of 3D cell culture systems have been investigated, to date, hydrogel-based scaffold systems appear to offer the greatest advantage for developing a wide-range of customizable, tissue-mimetic systems. However, current hydrogel systems are limiting and are associated with significant diffusion and scalability constraints. Thus, the research outlined in these studies is aimed at developing a novel 3D hydrogel system that is tailorable, tissue-mimetic, and permits long-term culture expansion for improved scalability of future MSC-derived clinical therapies. A number of parameters were investigated, including the dimensionality, architectural design, matrix binding epitopes, material, and mechanical properties of the hydrogel system. Notably, the micro- and macro- structural designs are critical.The 3D hydrogel system proposed was demonstrated as a system that can be utilized as a continuous “bioreactor” system to expand MSC populations that retain their viability and regenerative phenotype. A critical component of MSC regenerative potential that was investigated was the ability of the secretome to promote critical wound healing activity in secondary cell populations. The results demonstrated that retainment of more robust MSC populations was associated with increased secretion of regenerative factors. Moreover, MSCs in 3D were able to adapt to priming stimuli more readily, resulting in greater diversity of secreted factors that modulated keratinocyte epidermal regeneration activity. Ultimately, this system demonstrated the potential to be a more efficient and effective methodology for the culture of MSC populations and for the improved production of cell-based and/or acellular biologic therapies that can be tailored toward specific soft tissue and regenerative applications.
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Date
2023-05-31
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University of Kansas
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Keywords
Bioengineering, Biomedical engineering, Biologics, Biomaterials, Regenerative Medicine, Stem Cells, Tissue Engineering, Wound Healing