Designing collagens to shed light on the multi-scale structure-function mapping of matrix disorders.

Collagens are the most abundant structural proteins in the extracellular matrix of animals and play crucial roles in maintaining the structural integrity and mechanical properties of tissues and organs while mediating important biological processes. Fibrillar collagens have a unique triple helix structure with a characteristic repeating sequence of (Gly-X-Y)n. Variations within the repetitive sequence can cause misfolding of the triple helix, resulting in heritable connective tissue disorders. The most common variations are single-point missense mutations that lead to the substitution of a glycine residue with a bulkier amino acid (Gly â†’ X). In this review, we will first discuss the importance of collagen's triple helix structure and how single Gly substitutions can impact its folding, structure, secretion, assembly into higher-order structures, and biological functions. We will review the role of "designer collagens," i.e., synthetic collagen-mimetic peptides and recombinant bacterial collagen as model systems to include Gly â†’ X substitutions observed in collagen disorders and investigate their impact on structure and function utilizing in vitro studies. Lastly, we will explore how computational modeling of collagen peptides, especially molecular and steered molecular dynamics, has been instrumental in probing the effects of Gly substitutions on structure, receptor binding, and mechanical stability across multiple length scales.

Tissue Engineered 3D Constructs for Volumetric Muscle Loss.

Severe injuries to skeletal muscles, including cases of volumetric muscle loss (VML), are linked to substantial tissue damage, resulting in functional impairment and lasting disability. While skeletal muscle can regenerate following minor damage, extensive tissue loss in VML disrupts the natural regenerative capacity of the affected muscle tissue. Existing clinical approaches for VML, such as soft-tissue reconstruction and advanced bracing methods, need to be revised to restore tissue function and are associated with limitations in tissue availability and donor-site complications. Advancements in tissue engineering (TE), particularly in scaffold design and the delivery of cells and growth factors, show promising potential for regenerating damaged skeletal muscle tissue and restoring function. This article provides a brief overview of the pathophysiology of VML and critiques the shortcomings of current treatments. The subsequent section focuses on the criteria for designing TE scaffolds, offering insights into various natural and synthetic biomaterials and cell types for effectively regenerating skeletal muscle. We also review multiple TE strategies involving both acellular and cellular scaffolds to encourage the development and maturation of muscle tissue and facilitate integration, vascularization, and innervation. Finally, the article explores technical challenges hindering successful translation into clinical applications.