Advances in biomaterial-based cardiac organoids.

Cardiovascular disease (CVD) is one of the important causes of death worldwide. The incidence and mortality rates are increasing annually with the intensification of social aging. The efficacy of drug therapy is limited in individuals suffering from severe heart failure due to the inability of myocardial cells to undergo regeneration and the challenging nature of cardiac tissue repair following injury. Consequently, surgical transplantation stands as the most efficient approach for treatment. Nevertheless, the shortage of donors and the considerable number of heart failure patients worldwide, estimated at 26 million, results in an alarming treatment deficit, with only around 5000 heart transplants feasible annually. The existing major alternatives, such as mechanical or xenogeneic hearts, have significant flaws, such as high cost and rejection, and are challenging to implement for large-scale, long-term use. An organoid is a three-dimensional (3D) cell tissue that mimics the characteristics of an organ. The critical application has been rated in annual biotechnology by authoritative journals, such as Science and Cell. Related industries have achieved rapid growth in recent years. Based on this technology, cardiac organoids are expected to pave the way for viable heart repair and treatment and play an essential role in pathological research, drug screening, and other areas. This review centers on the examination of biomaterials employed in cardiac repair, strategies employed for the reconstruction of cardiac structure and function, clinical investigations pertaining to cardiac repair, and the prospective applications of cardiac organoids. From basic research to clinical practice, the current status, latest progress, challenges, and prospects of biomaterial-based cardiac repair are summarized and discussed, providing a reference for future exploration and development of cardiac regeneration strategies.

Restoration of spinal cord biophysical microenvironment for enhancing tissue repair by injury-responsive smart hydrogel.

Spinal cord injury (SCI) represents a central nervous system disaster, resulting in the destruction of spinal cord structure and function and the formation of an adverse microenvironment at the SCI site. Various biomaterial-based therapeutic strategies have been developed to repair SCI by bridging spinal cord lesions. However, constructing a favorable biophysical microenvironment with biomaterials for spinal cord regeneration remains challenging because of the unmatched mechanical and electrical transmission properties with native spinal cords and the supra- or subtherapeutic dose release of biological molecules independent of SCI activity. Herein, we developed a new hydrogel with mechanical properties and conductivities comparable to those of native spinal cords by controlling gelatin and PPy concentrations. To endow the hydrogel with a biological function, glutathione (GSH) was conjugated on the hydrogel through gelatin-derived amine groups and GSH-derived sulfhydryl groups to prepare an MMP-responsive hydrogel with a recombinant protein, GST-TIMP-bFGF. The MMP-responsive conductive hydrogel could release bFGF on-demand in response to the SCI microenvironment and provide a favorable biophysical microenvironment with comparable mechanical and electrical properties to native spinal cords. In SCI model rats, the MMP-responsive bionic mechanical and conductive hydrogel could inhibit MMPs levels, promote axon regeneration and angiogenesis, and improve locomotion function recovery after SCI.

A collagen microchannel scaffold carrying paclitaxel-liposomes induces neuronal differentiation of neural stem cells through Wnt/ß-catenin signaling for spinal cord injury repair.

Neural stem cells (NSCs) show potential for spinal cord injury (SCI) repair. However, the current challenge is to direct their differentiation into neurons in the lesion site. It has been demonstrated that transplanted NSCs primarily differentiated into astrocytes rather than neurons due to the adverse microenvironment. It was reported that microtubule-stabilizing agent paclitaxel (PTX) was able to reduce scarring and enhance intrinsic axon regeneration after SCI. In this study, the effect of PTX on NSC differentiation was studied. It was demonstrated for the first time that PTX could rescue myelin-inhibited neuronal differentiation of NSCs, and induced a higher neuronal differentiation as compared with that in normal microenvironment. Enhanced neuronal differentiation in normal microenvironment further validated that PTX was capable of inducing intrinsic neuronal differentiation of NSCs. Furthermore, a functional collagen scaffold was developed by loading PTX-encapsulated liposomes into a collagen microchannel scaffold, leading to a prolonged sustained release of PTX. When NSC-laden functional collagen scaffold was implanted into T8 complete transection site of rat spinal cord, the scaffold provided an instructive microenvironment for neuronal differentiation of NSCs, motor and sensory neuron regeneration, and axon extension. The neural regeneration eventually led to improvement in motor evoked potential and hindlimb locomotion recovery. Moreover, mRNA-Seq and western blotting results revealed that PTX-triggered neuronal differentiation occurred through Wnt/ß-catenin signaling pathway. Together, the collagen microchannel scaffold in combination with sustained release of therapeutic agents for inducing neuronal differentiation of NSCs is promising for SCI repair.

A modified collagen scaffold facilitates endogenous neurogenesis for acute spinal cord injury repair.

Due to irreversible neuronal loss and glial scar deposition, spinal cord injury (SCI) ultimately results in permanent neurological dysfunction. Neuronal regeneration of neural stem cells (NSCs) residing in the spinal cord could be an ideal strategy for replenishing the lost neurons and restore function. However, many myelin-associated inhibitors in the SCI microenvironment limit the ability of spinal cord NSCs to regenerate into neurons. Here, a linearly ordered collagen scaffold was used to prevent scar deposition, guide nerve regeneration and carry drugs to neutralize the inhibitory molecules. A collagen-binding EGFR antibody Fab fragment, CBD-Fab, was constructed to neutralize the myelin inhibitory molecules, which was demonstrated to promote neuronal differentiation and neurite outgrowth under myelin in vitro. This fragment could also specifically bind to the collagen and undergo sustained release from collagen scaffold. Then, the scaffolds modified with CBD-Fab were transplanted into an acute rat SCI model. The robust neurogenesis of endogenous injury-activated NSCs was observed, and these NSCs could not only differentiate into neurons but further mature into functional neurons to reconnect the injured gap. The results indicated that the modified collagen scaffold could be an ideal candidate for spinal cord regeneration after acute SCI. STATEMENTS OF SIGNIFICANCE: A linearly ordered collagen scaffold was specifically modified with collagen-binding EGFR antibody, allowed for sustained release of this EGFR neutralizing factor, to block the myelin associated inhibitory molecules and guide spinal cord regeneration along its linear fibers. Dorsal root ganglion neurons and neural stem cells induced by CBD-Fab exhibited enhanced neurite outgrowth and neuronal differentiation rate under myelin in vitro. Transplantation of the modified collagen scaffold with moderate EGFR neutralizing proteins showed greatest advantage on endogenous neurogenesis of injury-activated neural stem cells for acute spinal cord injury repair.