Fibrin hydrogels are an exciting platform for cell-based therapies, as they contain necessary cues for adhesion, can be remodeled by entrapped cells, and the biophysical properties can be modified with a plethora of strategies. Furthermore, fibrin acts as a provisional matrix in vivo for tissue regeneration. While the majority of studies seek to manipulate fibrin gel properties by changing the concentration of clotting proteins, these studies highlight our capacity to change bulk stiffness and fiber properties by supplementing the solutions with sodium chloride (NaCl). Physical properties including fiber thickness, porosity, compressive modulus, and fluid uptake capacity were dependent on NaCl content, with gels containing 2.60% (w/v) NaCl exhibiting compressive moduli threefold higher than gels without NaCl. These material properties, in turn, affected the gel morphology along with the osteogenic and pro-angiogenic response of entrapped mesenchymal stem/stromal cells (MSCs). The osteoconductivity of fibrin gels can be enhanced by inclusion of apatite-coated polymer substrata to nucleate mineral, while the efficacy of engineered fibrin gels to simultaneously deploy small molecules with cells to enhance endogenous angiogenic potential has been demonstrated. Collectively, these data demonstrate the broad capacity of engineered fibrin gels to regulate function of entrapped cells for use in tissue engineering and regenerative medicine.

Current treatment options for tissue loss or organ failure include organ/tissue transplantation of autografts/allografts, delivery of bioactive agents, and utilization of synthetic replacements composed of metals, polymers, and ceramics. However each strategy suffers from a number of limitations. The early attempts to overcome these drawbacks led to the emergence of tissue engineering that provided viable tissue substitutes using a combination of biomaterials, cells, and factors. This approach was ideally suited to repair damaged tissues; however the substitution and regeneration of large tissue volumes and multi-level tissues such as complex organ systems require more than optimal combinations of biomaterials and biologics.

‘Regenerative Engineering’ is aimed at creating large and complex tissue systems incorporating advances in material science, stem cell technology and developmental biology. We believe that recent breakthrough technologies in advanced materials science and nanotechnology allow us to recapitulate native tissues. The novel designer polymers incorporate bioactivity and physical features specific to a regeneration application. Overall, engineered materials and scaffolds afford selective control of cell sensitivity, and precise control of temporal and spatial stimulatory cues. We aim to build multi-level systems such as organs through location-specific topographies and physico-chemical cues incorporated into a continuous phase using a combination of classical top-down tissue engineering approach with bottom-up strategies used in regenerative biology.

Musculoskeletal tissues are critical to the normal functioning of an individual and following damage or degeneration show extremely limited endogenous regenerative capacity. The development of material and structural platforms to modulate stem cell behavior to enhance regeneration is an area of great interest. In this manuscript we cover some examples of material development, and incorporation of topographical and cytokine cues to modulate the differentiation of hard and soft musculoskeletal tissues such as bone, ligament and tendon.

The current gold-standard therapeutic strategies for bone grafts in the patient population are to use either allograft or autograft bone. Although these approaches have a long track record of utilization, neither is without risk to the patient, and there remains a desire in the field to improve treatment options. While there have been treatments approved by the FDA for full length growth factors and calcium salt-laden collagen sponges, these are not available for the entire population of potential bone graft patients. One viable strategy to focus on these concerns is to design an implantable bone graft substitute that can address all the negative drawbacks of autograft bone, allograft bone, and full length proteins. The work provides a preliminary investigation of synthetic, nanofiber-permeated, composite polymer/ceramic scaffold for bone repair using thermally induced phase separation, PLLA microspheres, and hydroxyapatite. The scaffolds as described have fiber diameters that mimic natural collagen ECM networks in bone as determined by scanning electron microscopy and will serve as the basis for future studies in substrate-guided bone tissue regeneration.