The fibrous architecture of the extracellular matrix (ECM) is recognized as an integral regulator of cell function. However, there is an unmet need to develop mechanically robust biomaterials mimicking nanofibrous tissue topography that are also injectable to enable minimally invasive delivery. In this study, we have developed a fibrous hydrogel composed of supramolecularly assembled hyaluronic acid (HA) nanofibers that exhibits mechanical integrity, shear-thinning behavior, rapid self-healing, and cytocompatibility. HA was modified with methacrylates to permit fiber photo-cross-linking following electrospinning and either “guest” adamantane or “host” β-cyclodextrin groups to guide supramolecular fibrous hydrogel assembly. Analysis of fibrous hydrogel rheological properties showed that the mixed guest–host fibrous hydrogel was more mechanically robust (6.6 ± 2.0 kPa, storage modulus (G′)) than unmixed guest hydrogel fibers (1.0 ± 0.1 kPa) or host hydrogel fibers (1.1 ± 0.1 kPa) separately. The reversible nature of the guest–host supramolecular interactions also allowed for shear-thinning and self-healing behavior as demonstrated by cyclic deformation testing. Human mesenchymal stromal cells (hMSCs) encapsulated in fibrous hydrogels demonstrated satisfactory viability following injection and after 7 days of culture (>85%). Encapsulated hMSCs were more spread and elongated when cultured in viscoelastic guest–host hydrogels compared to nonfibrous elastic controls, with hMSCs also showing significantly decreased circularity in fibrous guest–host hydrogels compared to nonfibrous guest–host hydrogels. Together, these data highlight the potential of this injectable fibrous hydrogel platform for cell and tissue engineering applications requiring minimally invasive delivery.
Volumetric muscle loss (VML) injuries are characterized by permanent loss of muscle mass, structure, and function. Hydrogel biomaterials provide an attractive platform for skeletal muscle tissue engineering due to the ability to easily modulate their biophysical and biochemical properties to match a range of tissue characteristics. In this work we successfully developed a mechanically tunable hyaluronic acid (HA) hydrogel system to investigate the influence of hydrogel stiffness on VML repair. HA was functionalized with photoreactive norbornene groups to create hydrogel networks that rapidly crosslink via thiol-ene click chemistry with tailored mechanics. Mechanical properties were controlled by modulating the amount of matrix metalloproteinase (MMP)-degradable peptide crosslinker to produce hydrogels with increasing elastic moduli of 1.1 ± 0.002, 3.0 ± 0.002, and 10.6 ± 0.006 kPa mimicking a relevant range of developing and mature muscle stiffnesses. Functional muscle recovery was assessed following implantation of the HA hydrogels by in situ photopolymerization into rat latissimus dorsi (LD) VML defects at 12 and 24 weeks post-injury. After 12 weeks, muscles treated with medium stiffness (3.0 kPa) hydrogels produced maximum isometric forces most similar to contralateral healthy LD muscles. This trend persisted at 24 weeks post-injury, suggestive of sustained functional recovery. Histological analysis revealed a significantly larger zone of regeneration with more de novo muscle fibers following implantation of medium stiffness hydrogels in VML-injured muscles compared to other experimental groups. Lower (low and medium) stiffness hydrogels also appeared to attenuate the chronic inflammatory response characteristic of VML injuries, displaying similar levels of macrophage infiltration and polarization to healthy muscle. Together these findings illustrate the importance of hydrogel mechanical properties in supporting functional repair of VML injuries.
The fibrous architecture of the extracellular matrix (ECM) is recognized as an integral regulator of cell function. However, there is an unmet need to develop mechanically robust biomaterials mimicking nanofibrous tissue topography that are also injectable to enable minimally invasive delivery. In this study we have developed a fibrous hydrogel composed of supramolecularly-assembled hyaluronic acid (HA) nanofibers that exhibits mechanical integrity, shear-thinning, rapid self-healing, and cytocompatibility. HA was modified with methacrylates to permit fiber photocrosslinking following electrospinning and either guest adamantane or host β-cyclodextrin groups to guide supramolecular fibrous hydrogel assembly. Analysis of fibrous hydrogel rheological properties showed that the mixed guest-host fibrous hydrogel was more mechanically robust (6.6 ± 2.0 kPa, storage modulus (G')) than unmixed guest hydrogel fibers (1.0 ± 0.1 kPa, G') or host hydrogel fibers (1.1 ± 0.1 kPa, G') separately. The reversible nature of the guest-host supramolecular interactions also allowed for shear-thinning and self-healing behavior as demonstrated by cyclic deformation testing. Human mesenchymal stromal cells (hMSCs) encapsulated in fibrous hydrogels demonstrated satisfactory viability following injection and after seven days of culture (> 85%). Encapsulated hMSCs were more spread and elongated when cultured in viscoelastic guest-host hydrogels compared to non-fibrous elastic controls, with hMSCs also showing significantly decreased circularity in fibrous guest-host hydrogels compared to non-fibrous guest-host hydrogels. Together, these data highlight the potential of this injectable fibrous hydrogel platform for cell and tissue engineering applications requiring minimally invasive delivery.
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