Generation of thick vascularized tissues that fully match the patient still remains an unmet challenge in cardiac tissue engineering. Here, a simple approach to 3D‐print thick, vascularized, and ...perfusable cardiac patches that completely match the immunological, cellular, biochemical, and anatomical properties of the patient is reported. To this end, a biopsy of an omental tissue is taken from patients. While the cells are reprogrammed to become pluripotent stem cells, and differentiated to cardiomyocytes and endothelial cells, the extracellular matrix is processed into a personalized hydrogel. Following, the two cell types are separately combined with hydrogels to form bioinks for the parenchymal cardiac tissue and blood vessels. The ability to print functional vascularized patches according to the patient's anatomy is demonstrated. Blood vessel architecture is further improved by mathematical modeling of oxygen transfer. The structure and function of the patches are studied in vitro, and cardiac cell morphology is assessed after transplantation, revealing elongated cardiomyocytes with massive actinin striation. Finally, as a proof of concept, cellularized human hearts with a natural architecture are printed. These results demonstrate the potential of the approach for engineering personalized tissues and organs, or for drug screening in an appropriate anatomical structure and patient‐specific biochemical microenvironment.
A small biopsy of an omental tissue is taken from patients. While the cells are reprogrammed to induce pluripotent stem cells and differentiate to cardiac and endothelial cells, the extra‐cellular matrix is processed into a thermoresponsive, hydrogel‐based bioink. These components are used to 3D‐print functional vascularized cardiac patches and even small scale, whole cellularized human hearts.
Despite incremental improvements in the field of tissue engineering, no technology is currently available for producing completely autologous implants where both the cells and the scaffolding ...material are generated from the patient, and thus do not provoke an immune response that may lead to implant rejection. Here, a new approach is introduced to efficiently engineer any tissue type, which its differentiation cues are known, from one small tissue biopsy. Pieces of omental tissues are extracted from patients and, while the cells are reprogrammed to become induced pluripotent stem cells, the extracellular matrix is processed into an immunologically matching, thermoresponsive hydrogel. Efficient cell differentiation within a large 3D hydrogel is reported, and, as a proof of concept, the generation of functional cardiac, cortical, spinal cord, and adipogenic tissue implants is demonstrated. This versatile bioengineering approach may assist to regenerate any tissue and organ with a minimal risk for immune rejection.
Fatty tissues are extracted from patients and the cellular and a‐cellular materials are separated. While the cells are reprogrammed to induced pluripotent stem cells (iPSCs), the extracellular matrix is processed to a personalized, nonimmunogenic hydrogel. The iPSCs are encapsulated within the hydrogel and differentiated to engineer autologous cardiac, cortical, dopaminergic, spinal cord, and adipogenic implants.
In a myocardial infarction, blood supply to the left ventricle is abrogated due to blockage of one of the coronary arteries, leading to ischemia, which further triggers the generation of reactive ...oxygen species (ROS). These sequential processes eventually lead to the death of contractile cells and affect the integrity of blood vessels, resulting in the formation of scar tissue. A new heart therapy comprised of cardiac implants encapsulated within an injectable extracellular matrix‐gold nanoparticle composite hydrogel is reported. The particles on the collagenous fibers within the hydrogel promote fast transfer of electrical signal between cardiac cells, leading to the functional assembly of the cardiac implants. The composite hydrogel is shown to absorb reactive oxygen species in vitro and in vivo in mice ischemia reperfusion model. The reduction in ROS levels preserve cardiac tissue morphology and blood vessel integrity, reduce the scar size and the inflammatory response, and significantly prevent the deterioration of heart function.
This study presents a new heart therapy comprised of cardiac implants encapsulated within an injectable extracellular matrix‐gold nanoparticle composite hydrogel in mice ischemia‐reperfusion model. The particles promote the fast transfer of electrical signal between cardiac cells, whereas the composite hydrogel can absorb reactive oxygen species. The reduction in reactive oxygen species levels can preserve cardiac tissue morphology and functionality.
Cell therapy using induced pluripotent stem cell‐derived neurons is considered a promising approach to regenerate the injured spinal cord (SC). However, the scar formed at the chronic phase is not a ...permissive microenvironment for cell or biomaterial engraftment or for tissue assembly. Engineering of a functional human neuronal network is now reported by mimicking the embryonic development of the SC in a 3D dynamic biomaterial‐based microenvironment. Throughout the in vitro cultivation stage, the system's components have a synergistic effect, providing appropriate cues for SC neurogenesis. While the initial biomaterial supported efficient cell differentiation in 3D, the cells remodeled it to provide an inductive microenvironment for the assembly of functional SC implants. The engineered tissues are characterized for morphology and function, and their therapeutic potential is investigated, revealing improved structural and functional outcomes after acute and chronic SC injuries. Such technology is envisioned to be translated to the clinic to rewire human injured SC.
In a novel approach to regenerate the injured spinal cord (SC) at the chronic stage, induced pluripotent stem cells are encapsulated in a hydrogel to potentially form patient‐specific implants. The cells are differentiated to SC motor neurons and form 3D neuronal networks that bridge over the injured axons. The implants reduce inflammation, enhance nerve regeneration, and significantly improve locomotion.
Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a ...pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.
One of the strategies for heart regeneration includes cell delivery to the defected heart. However, most of the injected cells do not form quick cell–cell or cell–matrix interactions, therefore, ...their ability to engraft at the desired site and improve heart function is poor. Here, the use of a microfluidic system is reported for generating personalized hydrogel‐based cellular microdroplets for cardiac cell delivery. To evaluate the system's limitations, a mathematical model of oxygen diffusion and consumption within the droplet is developed. Following, the microfluidic system's parameters are optimized and cardiac cells from neonatal rats or induced pluripotent stem cells are encapsulated. The morphology and cardiac specific markers are assessed and cell function within the droplets is analyzed. Finally, the cellular droplets are injected to mouse gastrocnemius muscle to validate cell retention, survival, and maturation within the host tissue. These results demonstrate the potential of this approach to generate personalized cellular microtissues, which can be injected to distinct regions in the body for treating damaged tissues.
An omentum specimen is extracted from the patient and while the extracellular matrix is processed into a personalized hydrogel, the cells are reprogrammed to become induced pluripotent stem cells and differentiate to cardiac cells. These are used in a microfluidics system to generate personalized hydrogel‐based cellular microdroplets for cardiac cell delivery.
Personalized hydrogels for engineering patient‐specific tissues are reported by Tal Dvir and co‐workers in article number 1803895. A small fatty tissue biopsy is taken from the patient by a minimally ...invasive procedure and the cellular and the a‐cellular materials then separated. While the cells are reprogrammed to become induced pluripotent stem cells (iPSCs), the a‐cellular material is processed into a personalized hydrogel. After re‐integration, it is possible to engineer any tissue type, including spinal cord implants.
Recently, the integration of electronic elements with cellular scaffolds has brought forth the ability to monitor and control tissue function actively by using flexible free-standing two-dimensional ...(2D) systems. Capabilities for electrically probing complex, physicochemical and biological three-dimensional (3D) microenvironments demand, however, 3D electronic scaffolds with well-controlled geometries and functional-component distributions. This work presents the development of flexible 3D electronic scaffolds with precisely defined dimensions and microelectrode configurations formed using a process that relies on geometric transformation of 2D precursors by compressive buckling. It demonstrates a capability to fabricate these constructs in diverse 3D architectures and/or electrode distributions aimed at achieving an enhanced level of control and regulation of tissue function relatively to that of other approaches. In addition, this work presents the integration of these 3D electronic scaffolds within engineered 3D cardiac tissues, for monitoring of tissue function, controlling tissue contraction through electrical stimulation, and initiating on-demand, local release of drugs, each through well-defined volumetric spaces. These ideas provide opportunities in fields ranging from in vitro drug development to in vivo tissue repair and many others.
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In article number 1900344, Tal Dvir and co‐workers take a biopsy of an omental tissue from patients. While the cells are reprogrammed to induced pluripotent stem cells and differentiate into ...cardiomyocytes and endothelial cells, the remaining extracellular matrix is processed into a thermoresponsive hydrogel. These personalized materials and cells are used as bioinks to print functional vascularized cardiac patches and small‐scale human hearts.
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