Article

Biomaterials for tissue repair

Authors:
To read the full-text of this research, you can request a copy directly from the author.

Abstract

Biomaterials can promote endogenous healing without delivering cells or therapeutics

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the author.

... Despite each anatomic site has distinctive character-istics, overall, the ECM is a dynamic and complex structure that provides physical support and spatial organization. The cells-surrounding matrix provides a microenvironment that acts controlling cell behaviour, including cell survival, adhesion, proliferation, migration, differentiation, and angiogenesis (Christman, 2019;Dickinson and Gerecht, 2016). Bone remodelling is an extremely coordinated continuous process concerning multiple cell types, including osteoblasts, osteoclasts, fibroblasts, endothelial cells and immune cells (Li et al., 2020). ...
... The fibrin network provides a physical support and a set of biological cues that modulate cell behaviour (Brown and Barker, 2014). It also contains numerous cell and ECM binding sites and is susceptible to proteolytic degradation that enables cell colonization and tissue remodelling (Brown and Barker, 2014;Christman, 2019). Fibrinolysis is extremely important in tissue engineering. ...
... ties as natural physical support that contains ECM binding sites and also releases biological cues to promote the regeneration process (Brown and Barker, 2014;Christman, 2019). Despite the recognized effectiveness of PRPs, there are multiple obtaining protocols resulting in several plasma preparations with different composition and biological properties. ...
Article
Background Scaffolds should have controllable degradation rate and allow cells to produce their own extracellular matrix. Platelet rich plasma (PRP) is a source of autologous growth factors and proteins embedded in a 3D fibrin scaffold. There is no consensus regarding the obtaining conditions and composition of PRPs. The aim of this study was to evaluate how the inclusion of leukocytes (L-PRP) in plasma rich in growth factors (PRGF) may alter the process of fibrinolysis. The effect of different combinations of cellular phenotypes with PRGF and L-PRP clots on both the fibrinolysis and matrix deposition process was also determined. Methods PRGF and L-PRP clots were incubated for 14 days and D-dimer and type I collagen were determined in their conditioned media to evaluate clots’ stability. For remodelling assays, gingival fibroblasts, alveolar osteoblasts and human umbilical vein endothelial cells (HUVEC) were seeded onto the two types of clots for 14 days. D-dimer, type I collagen, and laminin α4 were measured by ELISA kits in their conditioned media. Morphological and histological analysis were also performed. Cell proliferation was additionally determined . Results PRGF clots preserved their stability as shown by the low levels of both D-dimer and collagen type I compared to those obtained for L-PRP clots. The inclusion of both gingival fibroblasts and alveolar osteoblasts stimulated a higher fibrinolysis in the PRGF clots. In contrast to this, the degradation rates of both PRGF and L-PRP clots remained unchanged after culturing with the endothelial cells. In all cases, type I collagen and laminin α4 levels were in line with the degree of clots’ degradation. In all phenotypes, cell proliferation was significantly higher in PRGF than in L-PRP clots. Conclusion The inclusion of leukocytes in PRGF scaffolds reduced their stability, decreased cell number and slowed down cell remodelling.
... Meanwhile, the efficiency of transdifferentiating mesodermal MSCs into Schwann-like cells varies greatly due to the heterogeneity caused by various intrinsic and extrinsic factors 5,19 . Recent studies have shown that somatic cells, such as fibroblasts [20][21][22][23] and epidermal keratinocytes 24 , can be directly converted into NCSC-or Schwann cell precursor (SCP)-like cells 25,26 via introduction of a single/multiple transcriptional factors or nongenetic approaches, such as defined culture conditions, the use of a cocktail of small molecules, and tuning the mechanical properties (pore size, stiffness, etc.) of natural or synthetic biomaterials 20,24,[26][27][28] . ...
... Cell reprogramming is a process that reverts differentiated somatic cells into induced pluripotent stem cells (iPSCs), enabling the direct conversion from one cell lineage to another 27,28,50 . In tissue engineering and regenerative medicine, cell reprogramming provides a useful platform to generate a sufficient number of stem/progenitor and specialized cells with improved quality and functions for cell-based regenerative therapy 50 . ...
... In recent years, natural and synthetic biomaterial scaffolds have been explored as a novel paradigm to guide cell conversion or differentiation toward a specific cell lineage through changing their mechanical properties 27 . For instance, the use of soft hydrogel has been shown to facilitate iPSC generation through promoting mesenchymal-epithelial transition (MET) process 51 . ...
Article
Full-text available
Achieving a satisfactory functional recovery after severe peripheral nerve injuries (PNI) remains one of the major clinical challenges despite advances in microsurgical techniques. Nerve autografting is currently the gold standard for the treatment of PNI, but there exist several major limitations. Accumulating evidence has shown that various types of nerve guidance conduits (NGCs) combined with post-natal stem cells as the supportive cells may represent a promising alternative to nerve autografts. In this study, gingiva-derived mesenchymal stem cells (GMSCs) under 3D-culture in soft collagen hydrogel showed significantly increased expression of a panel of genes related to development/differentiation of neural crest stem-like cells (NCSC) and/or Schwann cell precursor-like (SCP) cells and associated with NOTCH3 signaling pathway activation as compared to their 2D-cultured counterparts. The upregulation of NCSC-related genes induced by 3D-collagen hydrogel was abrogated by the presence of a specific NOTCH inhibitor. Further study showed that GMSCs encapsulated in 3D-collagen hydrogel were capable of transmigrating into multilayered extracellular matrix (ECM) wall of natural NGCs and integrating well with the aligned matrix structure, thus leading to biofabrication of functionalized NGCs. In vivo, implantation of functionalized NGCs laden with GMSC-derived NCSC/SCP-like cells (designated as GiSCs), significantly improved the functional recovery and axonal regeneration in the segmental facial nerve defect model in rats. Together, our study has identified an approach for rapid biofabrication of functionalized NGCs through harnessing 3D collagen hydrogel-directed conversion of GMSCs into GiSCs.
... However, biomaterials pose a considerable challenge to this stipulation because of their often permanent and integrative nature. Many new biomaterials are being engineered for maximal integration with the host tissue (Wang et al., 2004;Moroni and Elisseeff, 2008) or designed to promote endogenous repair and regeneration (Editorial, 2009;Wu et al., 2018;Christman, 2019), thus complicating or eliminating the ability for participants to withdraw. Other products are designed to elicit minimal host-biomaterial interaction but remain permanent. ...
... However, not all technologies are growing costlier and more complex. Novel strategies are also aiming to simplify biomaterial products, instead using acellular, off-the-shelf biomaterials that unlock the body's own power for organization and endogenous selfrepair (Weber et al., 2013;Christman, 2019;Kirkton et al., 2019). Developing approaches that minimize cost, when possible, and ensuring that the population of research subjects is well-aligned with the potential patient population are important components of just and equitable distribution of these technologies. ...
Article
Full-text available
Biomaterials--from implanted iron teeth in the second century to intraocular lenses, artificial joints, and stents today--have long been used clinically. Today, biomaterials researchers and biomedical engineers are pushing beyond these inert synthetic alternatives and incorporating complex multifunctional materials to control biological interactions and direct physiological processes. These advances are leading to novel strategies for targeted drug delivery, drug screening, diagnostics and imaging, gene therapy, tissue regeneration, and cell transplantation. While the field has survived ethical transgressions in the past, the rapidly expanding scope of biomaterials science, combined with the accelerating clinical translation of this diverse field calls for urgent attention to the complex and challenging ethical dilemmas these advances pose. This perspective responds to this call, examining the intersection of research ethics -- the sets of rules, principles and norms guiding responsible scientific inquiry -- and ongoing advances in biomaterials. While acknowledging the inherent tensions between certain ethical norms and the pressures of the modern scientific and engineering enterprise, we argue that the biomaterials community needs to proactively address ethical issues in the field by, for example, updating or adding specificity to codes of ethics, modifying training programs to highlight the importance of ethical research practices, and partnering with funding agencies and journals to adopt policies prioritizing the ethical conduct of biomaterials research. Together these actions can strengthen and support biomaterials as its advances are increasingly commercialized and impacting the health care system.
... DNA hydrogel not only has advantages of common hydrogeldhigh water content, connectivity, consistency, high degree of flexibility, and good mechanical propertiesdbut it also preserves biological functions derived from DNAdsequence programmability, molecular recognition, excellent biocompatibility, and biodegradability. Compared with other hydrogel materials, DNA hydrogel has many advantages: self-assembly [2e4], programmable design [5,6], and self-healing [7,8]. DNA can bind with a variety of functional motif to obtain complex purposes, such as responding to signal stimuli [9]. ...
... We then fixed the RCA reaction time to 8 We demonstrated that we could produce DNA hydrogels with different microscopic characteristics by regulating RCA time, scaffold shape, and concentrations. We can use scaffold-net DNA hydrogels to regulate cell migration movement. ...
Article
Full-text available
DNA hydrogels have unique properties, such as specific identifiable molecular structures, programmable self-assembly, and excellent biocompatibility, which have led to increasing researches in the field of nanomaterials and biomedical over the past two decades. However, effective methods to regulate the microstructure of DNA hydrogels still lack, which limits their applications in tissue engineering. By introducing DNA scaffolds into rolling circle amplification (RCA) products and implementing rapid self-assembly strategy, we can produce a regulable new type scaffold-net DNA hydrogel in a short time. Scaffolds concentration and RCA time can regulate the microcharacteristics and physical properties of hydrogels. Scaffold-net DNA hydrogels will be a promising bionic platform for the studies of cancer cell metastatic and microenvironment biophysics.
... 6,10 Biomaterials are commonly developed into a three-dimensional matrix to reconstruct an in vivo microenvironment that promotes wound healing. [11][12][13] Such a matrix can promote cell infiltration and release growth factors and proteins to produce a dynamically-organized ...
... Understanding the important role of immune responses and manipulating the inherent properties of biomaterials to regulate the immune reaction are approaches to overcome the current bottleneck of skin repair and regeneration. 13 reiterated that an appropriately designed biomaterial scaffold can mimic the original healthy ECM so as to create a new microenvironment that will promote new tissue formation. Designing and manipulating the topological structure, surface chemistry, mechanical properties, as well as degradation rate of the biomaterials will enable efficient regeneration. ...
Article
The progress of biomaterials and tissue engineering has led to significant advances in wound healing, but the clinical therapy to regenerate perfect skin remains a great challenge. The implantation of biomaterial scaffolds to heal wounds inevitably leads to a host immune response. Many recent studies revealed that the immune system plays a significant role in both the healing process and the outcome. Immunomodulation or immuno-engineering has thus become a promising approach to develop pro-regenerative scaffolds for perfect skin regeneration. In this paper, we will review recent advancements in immunomodulating biomaterials in the field of skin repair and regeneration, and discuss strategies to modulate the immune response by tailoring the chemical, physical and biological properties of the biomaterials. Understanding the important role of immune responses and manipulating the inherent properties of biomaterials to regulate the immune reaction are approaches to overcome the current bottleneck of skin repair and regeneration.
... Although application of free vascularized bone grafts from distant sites may represent the most reliable procedure, it is associated with issues including the size and shape mismatch, bone resorption, and secondary morbidity (3). Regenerative medicine approaches involving delivery of cells to defect sites have generated disappointing and inconsistent results (4). While recombinant human bone morphogenetic protein-2 (BMP-2) is currently approved for the bone repair and regeneration, this therapeutic is associated with notable side effects (e.g., ectopic bone formation and bone resorption) and high cost (5,6). ...
... New biomaterials that can promote tissue repair and regeneration on their own without the need for cells or other therapeutics have emerged as a potentially powerful paradigm for regenerative medicine (4). Topographical cues rendered by biomaterials have been extensively investigated to guide cell response including adhesion, spreading, alignment, migration, and gene expression (9,10). ...
Article
Full-text available
Biomaterials without exogenous cells or therapeutic agents often fail to achieve rapid endogenous bone regeneration with high quality. Here, we reported a class of three-dimensional (3D) nanofiber scaffolds with hierarchical structure and controlled alignment for effective endogenous cranial bone regeneration. 3D scaffolds consisting of radially aligned nanofibers guided and promoted the migration of bone marrow stem cells from the surrounding region to the center in vitro. These scaffolds showed the highest new bone volume, surface coverage, and mineral density among the tested groups in vivo. The regenerated bone exhibited a radially aligned fashion, closely recapitulating the scaffold’s architecture. The organic phase in regenerated bone showed an aligned, layered, and densely packed structure, while the inorganic mineral phase showed a uniform distribution with smaller pore size and an even distribution of stress upon the simulated compression. We expect that this study will inspire the design of next-generation biomaterials for effective endogenous bone regeneration with desired quality.
... Although application of free vascularized bone grafts from distant sites may represent the most reliable procedure, it is associated with issues including the size and shape mismatch, bone resorption, and secondary morbidity (3). Regenerative medicine approaches involving delivery of cells to defect sites have generated disappointing and inconsistent results (4). While recombinant human bone morphogenetic protein-2 (BMP-2) is currently approved for the bone repair and regeneration, this therapeutic is associated with notable side effects (e.g., ectopic bone formation and bone resorption) and high cost (5,6). ...
... New biomaterials that can promote tissue repair and regeneration on their own without the need for cells or other therapeutics have emerged as a potentially powerful paradigm for regenerative medicine (4). Topographical cues rendered by biomaterials have been extensively investigated to guide cell response including adhesion, spreading, alignment, migration, and gene expression (9,10). ...
Article
Biomaterials without exogenous cells or therapeutic agents often fail to achieve rapid endogenous bone regeneration with high quality. Herein, we reported a new class of three-dimensional (3D) nanofiber scaffolds with hierarchical structure and controlled alignment for effective endogenous cranial bone regeneration. 3D scaffolds consisting of radially aligned nanofibers guided and promoted the migration of bone marrow stem cells from the surrounding region to the center in vitro. Such scaffolds showed the highest new bone volume, surface coverage, and mineral density among the tested groups in vivo. The regenerated bone exhibited a radially-aligned fashion, closely recapitulating the scaffold’s architecture. The organic phase in regenerated bone showed an aligned, layered, and densely packed structure, while the inorganic mineral phase showed a uniform distribution with smaller pore size and an even distribution of stress upon the simulated compression. We expect that this study will inspire the design of next-generation biomaterials for effective endogenous bone regeneration with desired quality.
... Delivering pro-healing extracellular matrix by intravascular infusion post injury may provide translational advantages for the healing of inflamed tissues 'from the inside out'. Extracellular matrices (ECMs) derived from decellularized tissues have shown promising results as tissue engineering scaffolds and as an acellular strategy for regenerative medicine [1][2][3][4][5] . In particular, decellularized ECM can be processed via enzymatic digestion into inducible hydrogels that can be injected for minimally invasive delivery to tissues [6][7][8][9] . ...
Article
Full-text available
Decellularized extracellular matrix in the form of patches and locally injected hydrogels has long been used as therapies in animal models of disease. Here we report the safety and feasibility of an intravascularly infused extracellular matrix as a biomaterial for the repair of tissue in animal models of acute myocardial infarction, traumatic brain injury and pulmonary arterial hypertension. The biomaterial consists of decellularized, enzymatically digested and fractionated ventricular myocardium, localizes to injured tissues by binding to leaky microvasculature, and is largely degraded in about 3 d. In rats and pigs with induced acute myocardial infarction followed by intracoronary infusion of the biomaterial, we observed substantially reduced left ventricular volumes and improved wall-motion scores, as well as differential expression of genes associated with tissue repair and inflammation. Delivering pro-healing extracellular matrix by intravascular infusion post injury may provide translational advantages for the healing of inflamed tissues ‘from the inside out’.
... For example, Wong et al. [250] have conjugated RGD-bearing magnetic nanoparticles (Fe 3 O 4 coated with silica) to increase RGD tether mobility, which can be decreased through the application of an external magnetic field, thus increasing MSC adhesion, spreading, and osteogenic differentiation. Furthermore, a "self-regeneration" biomaterial concept has recently been proposed, whereby the promotion of vascularization and bone formation can be achieved without the need for introducing cells or other therapeutics [251]. This strategy is based on the presence of layered topographic cues, particularly in biomaterials that arrange the nanomorphologic cues into layered three-dimensional (3D) structures. ...
Article
Full-text available
Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.
... 1.5.3 The material selection: Synthetic and natural materials in TERM Biomaterials have been used for over 20 years in tissue engineering and regenerative medicine to enhance tissue repair and to support transplantation of cells and/or growth factors [123]. While initially "inert" biomaterials were developed that elicit minimal immune response upon implantation, the emphasis has shifted in recent years to polymers, hydrogels, and other materials that can function as bioactive matrices [124]. ...
... These procedures typically suffer from drawbacks associated with high cost, prolonged and laborious ex vivo culture process, potential recipient rejection or permanent use of immunosuppressive therapies. 41,42 In the present study, ECFCs on fPFC were morphologically more For patients with CADs, the average WSS over the plaques has been reported to be 42% higher than the healthy region. 49 For CABG surgery, WSS is greater at the anastomotic site and is relatively low along the bed of the graft (up to 11 dynes/cm 2 ). ...
Article
Full-text available
Acellular vascular scaffolds with capture molecules have shown great promise in recruiting circulating endothelial colony forming cells (ECFCs) to promote in vivo endothelialization. A microenvironment conducive to cell spreading and differentiation following initial cell capture are key to the eventual formation of a functional endothelium. In this study, syndecan‐4 and stromal cell‐derived factor‐1 alpha were used to functionalize an elastomeric biomaterial composed of poly(glycerol sebacate), Silk Fibroin and Type I Collagen, termed PFC, to enhance ECFC‐material interaction. Functionalized PFC (fPFC) showed significantly greater ECFCs capture capability under physiological flow. Individual cell spreading area on fPFC (1474 ± 63 μm2) was significantly greater than on PFC (1187 ± 54 μm2) as early as 2 h, indicating enhanced cell–material interaction. Moreover, fPFC significantly upregulated the expression of endothelial cell specific markers such as platelet endothelial cell adhesion molecule (24‐fold) and Von Willebrand Factor (11‐fold) compared with tissue culture plastic after 7 days, demonstrating differentiation of ECFCs into endothelial cells. fPFC fabricated as small diameter conduits and tested using a pulsatile blood flow bioreactor were stable and maintained function. The findings suggest that the new surface functionalization strategy proposed here results in an endovascular material with enhanced endothelialization.
... Biomaterials have been used within the context of tissue engineering for over Justin X. Zhong and Preethi Raghavan contributed equally to this work. 20 years; however, this new approach seeks to utilize biomaterial platforms to influence endogenous immune cell populations and create pro-reparative microenvironments [15,16]. ...
Article
Full-text available
The immune system plays a crucial role during tissue repair and wound healing processes. Biomaterials have been leveraged to assist in this in situ tissue regeneration process to dampen the foreign body response by evading or suppressing the immune system. An emerging paradigm within regenerative medicine is to use biomaterials to influence the immune system and create a pro-reparative microenvironment to instigate endogenously driven tissue repair. In this review, we discuss recent studies that focus on immunomodulation of innate and adaptive immune cells for tissue engineering applications through four biomaterial-based mechanisms of action: biophysical cues, chemical modifications, drug delivery, and sequestration. These materials enable augmented regeneration in various contexts, including vascularization, bone repair, wound healing, and autoimmune regulation. While further understanding of immune-material interactions is needed to design the next generation of immunomodulatory biomaterials, these materials have already demonstrated great promise for regenerative medicine. Lay Summary The immune system plays an important role in tissue repair. Many biomaterial strategies have been used to promote tissue repair, and recent work in this area has looked into the possibility of doing repair by tuning. Thus, we examined the literature for recent works showcasing the efficacy of these approaches in animal models of injuries. In these studies, we found that biomaterials successfully tuned the immune response and improved the repair of various tissues. This highlights the promise of immune-modulating material strategies to improve tissue repair.
... Several recent observations made with implanted biomaterials suggest otherwise: an optimal size of 1.5 mm for spherical implants results in less leukocyte recruitment, 14 parallel uniaxial topography with characteristic lengths similar to the cellular length scale promotes macrophage polarization into an anti-inflammatory phenotype, 15 while excessively stiff hydrogel implants chronically recruit neutrophils and result in a loss of antiinflammatory macrophage markers. 16 In contrast, unaltered tissuederived extracellular matrix (ECM) scaffolds do not develop fibrous capsules after implantation, 17,18 demonstrating why it is critically important to consider these physical parameters in designing biomaterials 19,20 and regenerative therapies 21 that interact with the immune system. Despite these developments, we still do not have a complete understanding of innate immunity from a biophysical or mechanical perspective, especially considering that core neutrophil and macrophage functions such as migration [22][23][24] and phagocytosis 25,26 are intrinsically mechanical processes. ...
Article
Full-text available
Innate immunity forms the core of the human body's defense system against infection, injury, and foreign objects. It aims to maintain homeostasis by promoting inflammation and then initiating tissue repair, but it can also lead to disease when dysregulated. Although innate immune cells respond to their physical microenvironment and carry out intrinsically mechanical actions such as migration and phagocytosis, we still do not have a complete biophysical description of innate immunity. Here, we review how engineering tools can be used to study innate immune cell biophysics. We first provide an overview of innate immunity from a biophysical perspective, review the biophysical factors that affect the innate immune system, and then explore innate immune cell biophysics in the context of migration, phagocytosis, and phenotype polarization. Throughout the review, we highlight how physical microenvironments can be designed to probe the innate immune system, discuss how biophysical insight gained from these studies can be used to generate a more comprehensive description of innate immunity, and briefly comment on how this insight could be used to develop mechanical immune biomarkers and immunomodulatory therapies.
... [17,18] Tissue repair and regeneration aiming to restore damaged or diseased tissues and organs is a complex and dynamic process, in which various classes of cells and biomolecules are tightly interacted to achieve homeostasis by regulating tissue microenvironments. [19,20] The metabolic disturbance of biological signals or overexpression of specific factors at the molecular level is closely related to pathogenic factors and disease therapy. [21] In recent years, smart biomaterials capable of selective response to specific physiological signals or pathological differences have been developed for cell-specific and precise therapeutic systems to achieve better therapeutic effects. ...
Article
Full-text available
Polyurethanes have been broadly used as biomaterials in tissue repair and regeneration due to their preeminent biocompatibility and mechanical properties. However, traditional polyurethanes are not able to efficiently cope with the complexity of dynamic tissue microenvironments during the process of disease therapy. Physiologically responsive polyurethanes responding or reacting to biological signals or pathological abnormalities can change their physicochemical properties, enabling on‐demand release or intelligently promoting tissue regeneration. So far, the physiologically responsive polyurethanes have gained significant interest for applications in controlled drug delivery systems and tissue engineering in recent years. This review highlights the research advances in the design of the physiological‐responsive polyurethanes and their applications for tissue repair and regeneration, with particular attention to some representative examples such as pH‐, redox‐, temperature‐, and enzyme‐responsive polyurethanes. The key design principles and applications are illustrated in the treatment of retinal detachment, gastric ulcer, wound, myocardial infarction, lung injury, bone defect, and osteoarthritis. The challenges and future perspectives of the physiological‐responsive polyurethanes are finally discussed. Polyurethanes that are sensitive to biological signals or pathological abnormalities can change their physiochemical features to improve therapy efficacy and thus can act as a smart therapeutic platform. This review introduces the fabrication strategies of several physiologically responsive polyurethanes, followed by a discussion of their applications in tissue repair and regeneration.
... [12] ECMmimicking biomaterials that self-assemble upon injection can promote repair by restoring tissue mechanical properties, providing adhesion sites and functional cues to cells, modulating inflammation, and/or releasing bioactive compounds upon degradation. [13][14][15][16] Collagen hydrogels have shown promising results as biomaterials for cardiac repair through enhanced angiogenesis, polarization of wound healing macrophages, and myocardial salvage. [17] However, most collagen-based materials reported in the literature have been made from animal-derived collagen, which carries inherent immune risks for clinical use. ...
Article
Full-text available
Methylglyoxal (MG) production after myocardial infarction (MI) leads to advanced glycation end‐product formation, adverse remodeling, and loss of cardiac function. The extracellular matrix (ECM) is a main target for MG glycation. This suggests that ECM‐mimicking biomaterial therapies may protect the post‐MI environment by removing MG. In this study, mechanisms by which a recombinant human collagen type I hydrogel therapy confers cardioprotection are investigated. One‐week post‐MI, mice receive intramyocardial injection of hydrogel or PBS. The hydrogel improves border zone contractility after 2 days, which is maintained for 28 days. RNA sequencing shows that hydrogel treatment decreases the expression of erythroid differentiation regulator 1, a factor associated with apoptosis. Hydrogel treatment reduces cardiomyocyte apoptosis and oxidative stress at 2 days with greater myocardial salvage seen at 28 days. The hydrogel located at the epicardial surface is modified by MG, and less MG‐modified proteins are observed in the underlying myocardium of hydrogel‐treated mice. Biomaterials that can be a target for MG glycation may act as a sponge to remove MG from the myocardium post‐MI. This leads to less oxidative stress, greater survival and contractility of cardiomyocytes, which altogether suggests a novel mechanism by which biomaterials improve function of the infarcted heart.
... Currently, bone regeneration strategies loaded with growth factors or cells have been extensively studied. However, physical stimuli without cellular or biochemical transmission are also increasing, promising endogenous healing [68][69][70][71]. Since bone graft directly interacts with tissue fluid and cells after implantation, the overall structure of the scaffold will greatly affect the final bone repair effect. ...
Article
Full-text available
Polylactic acid–glycolic acid (PLGA) has been widely used in bone tissue engineering due to its favorable biocompatibility and adjustable biodegradation. 3D printing technology can prepare scaffolds with rich structure and function, and is one of the best methods to obtain scaffolds for bone tissue repair. This review systematically summarizes the research progress of 3D-printed, PLGA-based scaffolds. The properties of the modified components of scaffolds are introduced in detail. The influence of structure and printing method change in printing process is analyzed. The advantages and disadvantages of their applications are illustrated by several examples. Finally, we briefly discuss the limitations and future development direction of current 3D-printed, PLGA-based materials for bone tissue repair.
... The first generation of biomaterials was crucial for minimizing tissue reactivity. When the body does not completely absorb these compounds, a thin fibrous layer develops between them and the rest of the body [6]. The materials utilized to make this implant are essential to its success. ...
Article
Full-text available
Several developments have been taking place since the inception of biomaterials based on their types and are incorporated into various applicable areas; there is a subsequent rise in the applications in numerous domains, primarily in the medical industry. Advancements in modern technology have increased the accessibility to understand tissue generations and diseases and created opportunities for the use of biomaterials. Various materials for the purpose of compatibility with the human body to act as a replacement for soft and hard tissues have been designed. Biocompatibility of materials have met the requirements in orthopedics by their evolution from bioinert to third generation materials. This article provides a classification of biomaterials based on the material they are made of and their respective applications in cardiovascular systems, drug delivery, and orthodontics etc. Furthermore, various materials such as cholinium based biomaterials and Ti-based alloys with their descriptive properties and usages are included. A section of the study also elucidates the testing procedures of biomaterials. This review attempts to provide a clear and summarized overview of the progressive applicability of biomaterials.
... The increasing prevalence of tissue injuries is fueling the progress of biological treatments, less invasive procedures, and new approaches of personalized medicine (Orive and Desimone, 2017). An exciting approach to tissue engineering and regenerative medicine involves the use of biomaterials (Christman, 2019;Torres, et al., 2008), autologous therapies and cells as tissue scaffolds. ...
Article
The increasing prevalence of tissue injuries is fueling the development of autologous biological treatments for regenerative medicine. Here, we investigated the potential of three different bioinks based on the combination of gelatin and alginate (GA), enriched in either hydroxyapatite (GAHA) or hydroxyapatite and PRGF (GAHAP), as a favorable microenvironment for human dental pulp stem cells (DPSCs). Swelling behaviour, in vitro degradation and mechanical properties of the matrices were evaluated. Morphological and elemental analysis of the scaffolds were also performed along with cytocompatibility studies. The in vitro cell response to the different scaffolds was also assessed. Results showed that all scaffolds presented high swelling capacity, and those that contained HA showed higher Young's modulus. GAHAP had the lowest degradation rate and the highest values of cytocompatibility. Cell adhesion and chemotaxis were significantly increased when PRGF was incorporated to the matrices. GAHA and GAHAP compositions promoted the highest proliferative rate as well as significantly stimulated osteogenic differentiation. In conclusion, the enrichment with PRGF improves the regenerative properties of the composites favouring the development of personalized constructs.
... Many therapeutic strategies have been suggested to promote bone regeneration, including scaffolds (Lin et al., 2019;Zhang et al., 2019;Zhou et al., 2019), stem cells (Annamalai et al., 2019;Kim et al., 2019;Kim et al., 2020), and osteogenic factors (Naskar et al., 2017;Lee et al., 2020;Amirthalingam et al., 2021;Lee et al., 2021b). More recently, biomaterial scaffolds that can promote bone tissue repair on their own, without the need for delivering cells, have emerged as a potentially powerful paradigm for bone tissue engineering, due to their promising advantages of reduced cost and fewer translational barriers than other regenerative medicine strategies, such as cell-based therapy (Christman, 2019;Montoya et al., 2021). Thus, the development of scaffolds with appropriate biomaterials became one of the key success paths for bone tissue engineering (Bose et al., 2012;Kim et al., 2020). ...
Article
Full-text available
Silicon nitride (SiN [Si3N4]) is a promising bioceramic for use in a wide variety of orthopedic applications. Over the past decades, it has been mainly used in industrial applications, such as space shuttle engines, but not in the medical field due to scarce data on the biological effects of SiN. More recently, it has been increasingly identified as an emerging material for dental and orthopedic implant applications. Although a few reports about the antibacterial properties and osteoconductivity of SiN have been published to date, there have been limited studies of SiN-based scaffolds for bone tissue engineering. Here, we developed a silicon nitride reinforced gelatin/chitosan cryogel system (SiN-GC) by loading silicon nitride microparticles into a gelatin/chitosan cryogel (GC), with the aim of producing a biomimetic scaffold with antibiofilm and osteogenic properties. In this scaffold system, the GC component provides a hydrophilic and macroporous environment for cells, while the SiN component not only provides antibacterial properties and osteoconductivity but also increases the mechanical stiffness of the scaffold. This provides enhanced mechanical support for the defect area and a better osteogenic environment. First, we analyzed the scaffold characteristics of SiN-GC with different SiN concentrations, followed by evaluation of its apatite-forming capacity in simulated body fluid and protein adsorption capacity. We further confirmed an antibiofilm effect of SiN-GC against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as well as enhanced cell proliferation, mineralization, and osteogenic gene upregulation for MC3T3-E1 pre-osteoblast cells. Finally, we developed a bioreactor to culture cell-laden scaffolds under cyclic compressive loading to mimic physiological conditions and were able to demonstrate improved mineralization and osteogenesis from SiN-GC. Overall, we confirmed the antibiofilm and osteogenic effect of a silicon nitride reinforced cryogel system, and the results indicate that silicon nitride as a biomaterial system component has a promising potential to be developed further for bone tissue engineering applications.
... Many therapeutic strategies have been suggested to promote bone regeneration, including scaffolds (Lin et al., 2019;Zhang et al., 2019;Zhou et al., 2019), stem cells (Annamalai et al., 2019;Kim et al., 2019;Kim et al., 2020), and osteogenic factors (Naskar et al., 2017;Lee et al., 2020;Amirthalingam et al., 2021;Lee et al., 2021b). More recently, biomaterial scaffolds that can promote bone tissue repair on their own, without the need for delivering cells, have emerged as a potentially powerful paradigm for bone tissue engineering, due to their promising advantages of reduced cost and fewer translational barriers than other regenerative medicine strategies, such as cell-based therapy (Christman, 2019;Montoya et al., 2021). Thus, the development of scaffolds with appropriate biomaterials became one of the key success paths for bone tissue engineering (Bose et al., 2012;Kim et al., 2020). ...
Article
Full-text available
Silicon nitride (SiN [Si 3 N 4 ]) is a promising bioceramic for use in a wide variety of orthopedic applications. Over the past decades, it has been mainly used in industrial applications, such as space shuttle engines, but not in the medical field due to scarce data on the biological effects of SiN. More recently, it has been increasingly identified as an emerging material for dental and orthopedic implant applications. Although a few reports about the antibacterial properties and osteoconductivity of SiN have been published to date, there have been limited studies of SiN-based scaffolds for bone tissue engineering. Here, we developed a silicon nitride reinforced gelatin/chitosan cryogel system (SiN-GC) by loading silicon nitride microparticles into a gelatin/chitosan cryogel (GC), with the aim of producing a biomimetic scaffold with antibiofilm and osteogenic properties. In this scaffold system, the GC component provides a hydrophilic and macroporous environment for cells, while the SiN component not only provides antibacterial properties and osteoconductivity but also increases the mechanical stiffness of the scaffold. This provides enhanced mechanical support for the defect area and a better osteogenic environment. First, we analyzed the scaffold characteristics of SiN-GC with different SiN concentrations, followed by evaluation of its apatite-forming capacity in simulated body fluid and protein adsorption capacity. We further confirmed an antibiofilm effect of SiN-GC against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as well as enhanced cell proliferation, mineralization, and osteogenic gene upregulation for MC3T3-E1 pre-osteoblast cells. Finally, we developed a bioreactor to culture cell-laden scaffolds under cyclic compressive loading to mimic physiological conditions and were able to demonstrate improved mineralization and osteogenesis from SiN-GC. Overall, we confirmed the antibiofilm and osteogenic effect of a silicon nitride reinforced cryogel system, and the results indicate that silicon nitride as a biomaterial system component has a promising potential to be developed further for bone tissue engineering applications.
... The scaffolds can act as acellular material, or they can be combined with cells. Another possibility is loading scaffolds with soluble molecules such as antibiotics, chemotherapeutic agents and growth factors that are transported into the surrounding environment, providing the therapeutic or regenerative effect [1]. ...
Article
Full-text available
Tissue repair and regeneration is an interdisciplinary field focusing on developing bioactive substitutes aimed at restoring pristine functions of damaged, diseased tissues. Biomaterials, intended as those materials compatible with living tissues after in vivo administration, play a pivotal role in this area and they have been successfully studied and developed for several years. Namely, the researches focus on improving bio-inert biomaterials that well integrate in living tissues with no or minimal tissue response, or bioactive materials that influence biological response, stimulating new tissue re-growth. This review aims to gather and introduce, in the context of Italian scientific community, cutting-edge advancements in biomaterial science applied to tissue repair and regeneration. After introducing tissue repair and regeneration, the review focuses on biodegradable and biocompatible biomaterials such as collagen, polysaccharides, silk proteins, polyesters and their derivatives, characterized by the most promising outputs in biomedical science. Attention is pointed out also to those biomaterials exerting peculiar activities, e.g., antibacterial. The regulatory frame applied to pre-clinical and early clinical studies is also outlined by distinguishing between Advanced Therapy Medicinal Products and Medical Devices.
... Although cell delivery has been shown to have beneficial effects to some extent, the maturation level of the injected CMs, the risk of immune rejection, and tumor formation are still a big concern [17]. To that end, an appropriately designed acellular biomaterial could provide the cells in the infarcted tissue with a new microenvironment to promote regeneration and electrical signal propagation, avoiding the risks associated with cell-based therapies [246]. Furthermore, ECM protein engineering approaches [247] could be practiced to develop conductive ECM-based biomaterials for the effective delivery of CM proliferation cues such as agrin, which has been recently found as a stimulator for CM proliferation [248]. ...
Article
Myocardial infarction (MI) is still the leading cause of mortality worldwide. The success of cell-based therapies and tissue engineering strategies for treatment of injured myocardium have been notably hindered due to the limitations associated with the selection of proper cell source, lack of engraftment of engineered tissues, and biomaterials with the host myocardium, limited vascularity, as well as immaturity of injected cells. The first-generation approaches in cardiac tissue engineering (cTE) have mainly relied on the use of desired cells (e.g., stem cells) along with non-conductive natural or synthetic biomaterials for in vitro construction and maturation of functional cardiac tissues, followed by testing the efficacy of the engineered tissues in vivo. However, to better recapitulate the native characteristics and conductivity of cardiac muscle, recent approaches have utilized electroconductive biomaterials or nanomaterial components within engineered cardiac tissues. This review article will cover the recent advancements in the use of electrically conductive biomaterials in cTE. The specific emphasis will be placed on the use of different types of nanomaterials such as gold nanoparticles (GNPs), silicon-derived nanomaterials, carbon-based nanomaterials (CBNs), as well as electroconductive polymers (ECPs) for engineering of functional and electrically conductive cardiac tissues. We will also cover the recent progress in the use of engineered electroconductive tissues for in vivo cardiac regeneration applications. We will discuss the opportunities and challenges of each approach and provide our perspectives on potential avenues for enhanced cTE. Statement of significance : Myocardial infarction (MI) is still the primary cause of death worldwide. Over the past decade, electroconductive biomaterials have increasingly been applied in the field of cardiac tissue engineering. This review paper provides the readers with the leading advances in the in vitro applications of conductive biomaterials along with an in-depth discussion of injectable/transplantable electroconductive biomaterials and their delivery methods for in vivo MI treatment. The paper also discusses the gaps in the field and offer possible novel avenues for improved cardiac tissue engineering.
... Various bone defects that occur in the oral and skeletal systems of humans have increased yearly because of inflammation, tumors, or trauma. Small bone defects can be repaired via self-healing of natural tissues [1] or by filling with bioceramic particles such as bone-bonding hydroxyapatite (HA) [2,3]; however, the repair of large or complex bone defects and in particular the promotion of osteogenesis remain a worldwide clinical challenge. The development of organic/inorganic composite scaffolds has become the focus toward solving this challenge [4]. ...
Article
Scaffold degradation regulation has become the key aspects in promoting bone regeneration and reconstruction. In the study, a novel stepwise-degraded PLGA/PCL/HA:Yb/Ho/Zn (PPHZ) scaffold was designed to compare with the fast-degradable PLGA/HA:Yb/Ho/Zn (PLHZ) scaffold to investigate the effects of scaffold degradation regulation on osteogenesis and to trace the scaffold degradation process. Micro-CT reconstruction, confocal fluorescence imaging, and histological sections were used for the analyses of the harvested animal samples, which demonstrated that the degradation regulated stepwise-degraded PPHZ scaffold maintaining higher mechanical strength and longer scaffold integrity is more advantageous for in vivo osteogenesis than the fast-degradable PLHZ scaffold. Meanwhile, the multifunctional HZ particles would help the anti-infection and tracking the distribution during scaffold degradation. The PPHZ scaffold may benefit future repair of anti-infective bone defects and in vivo multimodal tracking.
... These porous hydrogels exhibit shear-thinning behavior, are inherently modular, and because of the interstitial space between the packed HMPs they possess significant porosity that is important for tissue repair and reduced inflammation not only in the brain but also in other organs (Madden et al., 2010;Tokatlian et al., 2014). In a specific example, an HA microparticle hydrogel injected in a stroke cavity reduced astrogliosis and modulated neuroinflammation, illuminating the critical role of biomaterial design in tissue repair (Christman, 2019;Sideris et al., 2019). ...
Article
Full-text available
Numerous surgical procedures are daily performed worldwide to replace and repair damaged tissue. Tissue engineering is the field devoted to the regeneration of damaged tissue through the incorporation of cells in biocompatible and biodegradable porous constructs, known as scaffolds. The scaffolds act as host biomaterials of the incubating cells, guiding their attachment, growth, differentiation, proliferation, phenotype, and migration for the development of new tissue. Furthermore, cellular behavior and fate are bound to the biodegradation of the scaffold during tissue generation. This article provides a critical appraisal of how key biomaterial scaffold parameters, such as structure architecture, biochemistry, mechanical behavior, and biodegradability, impart the needed morphological, structural, and biochemical cues for eliciting cell behavior in various tissue engineering applications. Particular emphasis is given on specific scaffold attributes pertaining to skin and brain tissue generation, where further progress is needed (skin) or the research is at a relatively primitive stage (brain), and the enumeration of some of the most important challenges regarding scaffold constructs for tissue engineering.
... Accordingly, in order to restore functionality of bone, the use of implants has become a standard solution for orthopaedic applications, such as spinal fusion surgery [4][5][6][7]. Hence, it is essential to develop implants that are biomechanically optimized to provide safe, stable and long-lasting attachment between implant and bone tissue under environmental stresses, and the choice of appropriate biomaterials became one of the key success paths for orthopaedic implants [8][9][10][11]. ...
Article
Full-text available
A variety of novel biomaterials are emerging as alternatives to conventional metals and alloys, for use in spinal implants. These promise potential advantages with respect to e.g. elastic modulus compatibility with the host bone, improved radiological imaging or enhanced cellular response to facilitate osseointegration. However, to date there is scarce comparative data on the biological response to many of these biomaterials that would give insights into the relative level of bone formation, resorption inhibition and inflammation. Thus, in this study, we aimed to evaluate and compare the in vitro biological response to standard discs of four alternative biomaterials: polyether ether ketone (PEEK), zirconia toughened alumina (ZTA), silicon nitride (SN) and surface-textured silicon nitride (ST-SN), and the reference titanium alloy Ti6Al4V (TI). Material-specific characteristics of these biomaterials were evaluated, such as surface roughness, wettability, protein adsorption (BSA) and apatite forming capacity in simulated body fluid. The activity of pre-osteoblasts seeded on the discs was characterized, by measuring viability, proliferation, attachment and morphology. Then, the osteogenic differentiation of pre-osteoblasts was compared in vitro from early to late stage by Alizarin Red S staining and real-time PCR analysis. Finally, osteoclast activity and inflammatory response were assessed by real-time PCR analysis. Compared to TI, all other materials generally demonstrated a lower osteoclastic activity and inflammatory response. ZTA and SN showed generally an enhanced osteogenic differentiation and actin length. Overall, we could show that SN and ST-SN showed a higher osteogenic effect than the other reference groups, an inhibitive effect against bone resorption and low inflammation, and the results indicate that silicon nitride has a promising potential to be developed further for spinal implants that require enhanced osseointegration.
Article
Fabricating bioartificial bone graft ceramics retaining structural, mechanical, and bone induction properties akin to those of native stem-cell niches is a major challenge in the field of bone tissue engineering and regenerative medicine. Moreover, the developed materials are susceptible to microbial invasion leading to biomaterial-centered infections which might limit their clinical translation. Here, we successfully developed biomimetic porous scaffolds of polyurethane-reinforcedL-cysteine-anchored polyaniline capped strontium oxide nanoparticles to improve the scaffold's biocompatibility, osteo-regeneration, mechanical, and antibacterial properties. The engineered nanocomposite substrate PU/L-Cyst-SrO2 @PANI (0.4 wt%) significantly promotes bone repair and regeneration by modulating osteolysis and osteogenesis. ALP activity, collagen-I, ARS staining, as well as biomineralization of MC3T3-E1 cells, were used to assess the biocompatibility and cytocompatibility of the developed scaffolds in vitro, confirming that the scaffold provided a favorable microenvironment with a prominent effect on cell growth, proliferation, and differentiation. Furthermore, osteogenic protein markers were studied using qRT-PCR with expression levels of runt-related transcription factor 2 (RUNX2), secreted phosphoprotein 1 (Spp-I), and collagen type I (Col-I). The overall results suggest that PU/L-Cyst-SrO2 @PANI (0.4 wt%) scaffolds showed superior interfacial biocompatibility, antibacterial properties, load-bearing ability, and osteoinductivity as compared to pristine PU. Thus, prepared bioactive nanocomposite scaffolds perform as a promising biomaterial substrate for bone tissue regeneration.
Article
Cardiovascular disease is a leading cause of disability and death worldwide. Although the survival rate of patients with heart diseases can be improved with contemporary pharmacological treatments and surgical procedures, none of these therapies provide a significant improvement in cardiac repair and regeneration. Stem cell‐based therapies are a promising approach for functional recovery of damaged myocardium. However, the available stem cells are difficult to differentiate into cardiomyocytes, which result in the extremely low transplantation efficiency. Nanomaterials are widely used to regulate the myocardial differentiation of stem cells, and play a very important role in cardiac tissue engineering. This study discusses the current status and limitations of stem cells and cell‐derived exosomes/micro RNAs based cardiac therapy, describes the cardiac repair mechanism of nanomaterials, summarizes the recent advances in nanomaterials used in cardiac repair and regeneration, and evaluates the advantages and disadvantages of the relevant nanomaterials. Besides discussing the potential clinical applications of nanomaterials in cardiac therapy, the perspectives and challenges of nanomaterials used in stem cell‐based cardiac repair and regeneration are also considered. Finally, new research directions in this field are proposed, and future research trends are highlighted. Nanomaterials are widely used in cardiac repair and regeneration. In this review, the current status and limitations of stem cell‐based cardiac therapy as well as the recent advances in nanomaterials and their advantages and disadvantages are summarized. Moreover, challenges of nanomaterials used in stem cell‐based therapeutics are discussed, and new research directions in cardiac tissue engineering are proposed.
Article
Repeating l- and d-chiral configurations determine polylactide (PLA) stereochemistry, which affects its thermal and physicochemical properties, including degradation profiles. Clinically, degradation of implanted PLA biomaterials promotes prolonged inflammation and excessive fibrosis, but the role of PLA stereochemistry is unclear. Additionally, although PLA of varied stereochemistries causes differential immune responses in vivo, this observation has yet to be effectively modeled in vitro. A bioenergetic model was applied to study immune cellular responses to PLA containing >99% l-lactide (PLLA), >99% d-lactide (PDLA), and a 50/50 melt-blend of PLLA and PDLA (stereocomplex PLA). Stereocomplex PLA breakdown products increased IL-1β, TNF-α, and IL-6 protein levels but not MCP-1. Expression of these proinflammatory cytokines is mechanistically driven by increases in glycolysis in primary macrophages. In contrast, PLLA and PDLA degradation products selectively increase MCP-1 protein expression. Although both oxidative phosphorylation and glycolysis are increased with PDLA, only oxidative phosphorylation is increased with PLLA. For each biomaterial, glycolytic inhibition reduces proinflammatory cytokines and markedly increases anti-inflammatory (IL-10) protein levels; differential metabolic changes in fibroblasts were observed. These findings provide mechanistic explanations for the diverse immune responses to PLA of different stereochemistries and underscore the pivotal role of immunometabolism in the biocompatibility of biomaterials applied in medicine.
Article
Cell therapy has significant therapeutic potential but is often limited by poor donor cell retention and viability at the host implantation site. Biomaterials can improve cell retention by providing cells with increased cell-cell and cell-matrix contacts and materials that allow three-dimensional cell culture to better recapitulate native cell morphology and function. In this study, we engineered a scaffold that allows for cell encapsulation and sustained three-dimensional cell culture. Since cell therapy is largely driven by paracrine secretions, the material was fabricated by electrospinning to have a large internal surface area, micrometer-thin walls, and nanoscale surface pores to allow for nutrient exchange without early cell permeation. The material is degradable, which allows for less invasive removal of the implant. Here, a biodegradable poly(lactic-co-glycolic acid) (PLGA) microtube array membrane was fabricated. In vitro testing showed that the material supported the culture of human dermal fibroblasts for at least 21 days, with paracrine secretion of pro-angiogenic FGF2. In vivo xenotransplantation of human cells in an immunocompetent mouse showed that donor cells could be maintained for more than one month and the material showed no obvious toxicity. Analysis of gene expression and tissue histology surrounding the implant showed that the material produced muted inflammatory and immune responses compared to a permanent implant and increased markers of angiogenesis.
Article
Full-text available
There is significant interest in the role of stem cells in cardiac regeneration, and yet little is known about how cardiac disease progression affects native cardiac stem cells in the human heart. In this brief report, cardiac mesenchymal stem cell-like cells (CMSCLC) from the right atria of a 21-year-old female patient with a bicuspid aortic valve and aortic stenosis (referred to as biscuspid aortic valve disease BAVD-CMSCLC), were compared with those of a 78-year-old female patient undergoing coronary artery bypass surgery (referred to as coronary artery disease CAD-CMSCLC). Cells were analyzed for expression of MSC markers, ability to form CFU-Fs, metabolic activity, cell cycle kinetics, expression of NANOG and p16, and telomere length. The cardiac-derived cells expressed MSC markers and were able to form CFU-Fs, with higher rate of formation in CAD-CMSCLCs. BAVD-CMSCLCs did not display normal MSC morphology, had a much lower cell doubling rate, and were less metabolically active than CAD-CMSCLCs. Cell cycle analysis revealed a population of BAVD-CMSCLC in G2/M phase, whereas the bulk of CAD-CMSCLC were in the G0/G1 phase. BAVD-CMSCLC had lower expression of NANOG and shorter telomere lengths, but higher expression of p16 compared with the CAD-CMSCLC. In conclusion, BAVD-CMSCLC have a prematurely aged phenotype compared with CAD-CMSCLC, despite originating from a younger patient.
Article
Skin regeneration is a matter of high concern since many individuals suffer from skin damage. To date, the concept of protein-based artificial skin scaffolds have been successfully applied and proven in skin regeneration. However, realizing a skin tissue scaffold with a skin-like extracellular matrix (ECM) that combines low price, good biocompatibility, excellent antibacterial properties, good cell adhesion, and strong mechanical properties is still a major challenge. In this study, inexpensive silk sericin (SS) protein-based artificial skin nanofiber scaffolds (NFSs) with excellent biological activity, no immune rejection, and high mechanical strength were fabricated via microfluidic blow-spinning (MBS). In particular, the as-prepared NFS was transformed from a random coil structure to a β-sheet structure by using the MBS in high-speed shear chips to improve its stability and mechanical strength. Additionally, through in vitro and in vivo studies, it was shown that SS protein-based artificial skin NFSs possessed excellent antibacterial effects and degradability properties, as well as accelerated tissue granulation growth, effectively promoting full skin wound healing and skin regeneration for medical problems worldwide. Thus, this skin ECM-inspired NFS offers new perspectives for accelerating wound healing and tissue regeneration and provides potential applications for clinical medicine.
Preprint
Full-text available
Chronic inflammation is a major concern after total joint replacements (TJRs), as it is associated with bone loss, limited bone-implant integration (osseointegration), implant loosening and failure. Inflammation around implants could be directed away from adverse outcomes and toward enhanced osseointegration and improved surgical outcome. Activated macrophages exposed to polyethylene particles play a dominant inflammatory role, and exhibit elevated mitochondrial oxidative phosphorylation (OXPHOS) whose role is unclear. By probing the contribution of the electron transport chain (ETC), we show that increased oxygen consumption does not contribute to bioenergetic (ATP) levels in fibroblasts and primary bone marrow-derived macrophages activated by polyethylene particles. Rather, it generates reactive oxygen species (ROS) at complex I by increasing mitochondrial membrane potential in macrophages. Inhibition of OXPHOS in a dosedependent manner without affecting glycolysis was accomplished by targeting complex I of the ETC using either rotenone or metformin. Metformin decreased mitochondrial ROS and, subsequently, expression of proinflammatory cytokines, including IL-1β, IL-6 and MCP-1 but not TNF-a in macrophages. These results highlight the contribution of mitochondrial bioenergetics to activation of immune cells by polyethylene wear particles, offering new opportunities to modulate macrophage states toward desired clinical outcomes.
Article
The rapid development of biomedical materials and tissue engineering technology has played an increasingly important role in the process of tissue repair in recent years. Smart‐responsive hydrogels are three‐dimensional network structures formed by cross‐linking of hydrophilic polymers. In addition to having conventional hydrogels that approximate the natural extracellular matrix structure and serve as delivery vehicles for functional molecules (drugs and proteins). More importantly, smart‐responsive hydrogels can achieve relevant changes in material morphology or properties under the conditions of changes in physical, chemical, and biological factors, thereby achieving controlled functional molecules release. It is more urgent to design and build smart‐responsive hydrogels to achieve precise tissue repair with the introduction of the concept of precision medicine and drug delivery. In this review, we highlight different types of smart‐responsive hydrogels and their mechanisms of response to different stimuli and discuss their potential for application in different types of tissue repair, such as chronic wound repair, damaged heart tissue repair, brain nerve tissue repair, and other fields. Finally, we present the prospects of smart‐responsive hydrogels in tissue repair. In general, the current progress in the application of smart‐responsive hydrogels in tissue repair lays the foundation for future applications in other diseases. Smart‐responsive hydrogels can sense the small changes in the surrounding microenvironment and enable precise and controllable release of functional molecules. Smart‐responsive hydrogels with various response mechanisms have attracted extensive attention in the field of tissue repair. We believe that they can be applied in a wider range of fields including but not limited to tissue repair in the future.
Article
Several researches have demonstrated that synthetic hydrogels can mimic the mechanical and physicochemical properties of native extracellular matrices and act as cell‐scaffold. The biointerface can influence over tissue activities such as adhesion, signaling, cell–cell communications, and proliferation. In this work, the behavior of human embryonic kidney cells (HEK293) in contact with hydrogel surfaces based on poly‐N‐isopropylacrylamide (PNIPAM) and copolymers is studied. Ionic and neutral hydrogel surfaces are synthesized by free radical polymerization and characterized by Fourier‐transform infrared spectroscopy, swelling capacity, and wettability at culture conditions. Viability, proliferation, and bioadhesive capacity are analyzed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and Neutral Red assays, [3H]‐thymidine technique, Acridine Orange and Hoechst dye. Noncytotoxic and proliferative effects are observed in all cases. HEK293 cells are mainly adapted and adhered on neutral and low ionic charge surfaces showing typical cell morphology, and normal mitotic rates. While, lower adhesion, abnormal nuclear and cytoplasmic morphologies with mitotic/fragmentation processes are observed after contact with high ionic surfaces. The cellular cycle after cultive on PNIPAM, assessed by flow cytometry, is not affected regarding control surfaces (polystyrene). Therefore, hydrogel surfaces with neutral and low ionic charges can be apt to in vitro tissue development and possible applications of biomedical treatments. Biointerface of renal cells growing on hydrogel surfaces based on N‐isopropylacrylamide (NIPAM) and copolymers is analyzed. Cells are adapted to hydrophobic surface (contact angles > 50°) with low ionic charge or neutral. Normal cell cycle is observed in contact with poly‐NIPAM. Cationic surfaces alter the cell growing: low adhesion, abnormal nuclear and cytoplasmic morphologies, and mitotic/fragmentation process are observed.
Article
A hierarchical porous polymer film that can provide a balance of mechanical properties and specific surface areas and sustain cell functions has become a major target for material scientists and bioengineers in the past decade. However, the limited availability of materials that exhibit high mechanical performance and easily form hierarchical porous structures hinder the progress in practical application. Here, we show the design of a polyhedral oligomeric silsesquioxane (POSS) hybrid polymer by incorporating a bi-functional glycidyl-propyl POSS (G-POSS) into the epoxy polymer backbone, in which POSS functions as both a nanofiller to reinforce the mechanical performance and as the polarity mediator to induce self-assembly of the polymer chains into a three-dimensional (3D) connected porous structure. Nanoindentation shows that the incorporation of POSS leads to a 25 and 36% increase in modulus and hardness, respectively. Scanning electron microscopy results show that POSS helps tune the hydrophobicity of the polymer and assists in the interface assembly, allowing easy formation of a densely packed two-dimensional or 3D hierarchical porous structure. Culture of mouse embryonic fibroblast cells demonstrates that the hybrid polymer scaffold provides prominent advantages ranging from enhanced cell adhesion to proliferation. Particularly, the 3D hierarchical porous film allows good nutrient supply and cell communication, which better mimics the in vivo microenvironment with less cell morphology change during cell proliferation. Hence, the successful integration of high material strength and easy formation of an interconnected porous structure shows that POSS hybrid polymers have strong potential for applications in the fabrication of cell culture platforms and future translation in tissue repair and regeneration.
Article
A new trend in biomaterials synthesis is harnessing the production of microorganisms, owing to the low cost and sustainability. Because microorganisms use DNA as a production code, it is possible for humans to reprogram these cells and thus build living factories for the production of biomaterials. Over the past decade, advances in genetic engineering have enabled the development of various intriguing biomaterials with useful properties, with commercially available biomaterials representing only a few of these. In this review, we discuss the common strategies for the production of bulk and commodity biogenic polymers, and highlight several notable approaches such as modular protein engineering and pathway optimization in achieving these goals. We finally investigate the available synthetic biology tools that allow engineering of living materials, and discuss how this emerging class of materials has expanded the application scope of biomaterials.
Article
Full-text available
hierarchical porous bioceramics; bone defects; bone infection; in situ regeneration of bone; microenvironment; drug delivery
Article
Elastic composite scaffolds are used to mimic extracellular matrix in tissue regeneration. They are composed of synthetic elastomers in favor of natural elastin. Many elastomers require thermal polymerization for fiber stabilization. If the scaffold contains protein, additional treatments are required for stabilization. These treatments may modify the structure and function of the scaffold. In the present study a protein-elastomeric polymer composite of poly (glycerol sebacate), (PGS), silk fibroin, and type I collagen (termed PFC) was used as a model material to investigate a new method to improve stabilization of electrospun fibers. The purpose of this study was to optimize conditions in order to reduce internal flow of an elastomeric prepolymer during fiber fabrication. Co-electrospun sacrificial poly (ethylene oxide) (PEO) was used to provide scaffold fiber stabilization during fiber formation in order to test different protocols to prevent fiber fusion. Using PEO at a 1:1 ratio with PFC followed by glutaraldehyde treatment, removal of PEO and heat treatment to polymerize PGS resulted in the most stable and consistent fiber morphology. Functionally, scaffolds had increased porosity and improved cell infiltration. The study provides an improved procedure for fabrication of composite electrospun scaffolds requiring stabilization by both chemical and thermal methods.
Article
Polysulfone (PSF) as an expected potential biomaterial matches well with the urgent demand in biomedical applications on account of outstanding mechanical and chemical compatibility. In this review, the classification of some biological modifiers by the flow mosaic model was described. Then, several distinct modification approaches to PSF were introduced in detail, including blending, surface coating, and grafting. Moreover, diverse biomedical applications (hemodialysis, membrane oxygenator, cartilage scaffold, and so on) and up-to-date explorations were exhaustively presented to provide more information for further researches. Finally, the challenges in biomedical modifications of PSF were summarized and the potential application in biomedicine was forecasted.
Article
Either oriented architecture or viscoelasticity is pivotal to neurogenesis, thus, native neural extracellular matrix derived-hyaluronan hydrogels with nano-orientation and viscoelasticity recapitulated might be instructive for neurogenesis, however it is still unexploited. Herein, based on aldehyde-methacrylate difunctionalized hyaluronan, by integrating imine kinetic modulation and microfluidic biofabrication, we construct a hydrogel system with orthogonal viscoelasticity and nano-topography. We then find the positive synergy effects of matrix nano-orientation and viscoelasticity not only on neurites outgrowth and elongation of neural cells, but also on neuronal differentiation of stem cells. Moreover, by implanting viscoelastic and nano-aligned hydrogels into lesion sites, we demonstrate the enhanced repair of spinal cord injury, including ameliorated pathological microenvironment, facilitated endogenous neurogenesis and functional axons regeneration as well as motor function restoration. This work supplies universal platform for preparing neuronal inducing hyaluronan-based hydrogels which might serve as promising therapeutic strategies for nerve injury.
Article
A promising paradigm to regenerative medicine involves the application of biomaterials, which makes a spurt of progress in the past 20 years. Of various biomaterials, decellularized biomaterials possess good biocompatibility and great potential for clinical translation. The role of decellularized biomaterials in tissue repair and regeneration is not just the structure and delivering bioactive matters, what's even important, the interaction between biomaterials and the internal environment, especially the scaffold-immune system interactions, which is the initial response to in vivo implantation. Consequently, we have reviewed the immunogenicity of decellularized scaffolds derived from various tissues and organs, and immunomodulatory effects of decellularized scaffolds in the view of innate and adaptive immune systems. Finally, we discuss the influence factors of host responses mediated by decellularized biomaterials. Decellularized scaffold-immune interactions can provide important mechanistic insight into the development of decellularized materials in vivo, penetrating into the knowledge is the necessary precondition for the clinical translation.
Article
Decellularized tissue is expected to be utilized as a regenerative scaffold. However, the migration of host cells into the central region of the decellularized tissues is minimal because the tissues are mainly formed with dense collagen and elastin fibers. This results in insufficient tissue regeneration. Herein, it is demonstrated that host cell migration can be accelerated by using decellularized tissue with a patterned pore structure. Patterned pores with inner diameters of 24.5 ± 0.4 μm were fabricated at 100, 250, and 500 μm intervals in the decellularized vascular grafts via laser ablation. The grafts were transplanted into rat subcutaneous tissue for 1, 2, and 4 weeks. All the microporous grafts underwent faster recellularization with macrophages and fibroblast cells than the non-porous control tissue. In the case of non-porous tissue, the cells infiltrated approximately 50% of the area four weeks after transplantation. However, almost the entire area was occupied by the cells after two weeks when the micropores were aligned at a distance of less than 250 μm. These results suggest that host cell infiltration depends on the micropore interval, and a distance shorter than 250 μm can accelerate cell migration into decellularized tissues.
Article
Full-text available
Osteopontin (OPN) is an important protein for mediating cell behaviour on biomaterials. However, the interactions between the chemical groups on the biomaterial surface and OPN still need to be further clarified, which has restricted the application of OPN in biomaterial functionalization. In the present study, we developed different self-assembled monolayers (SAMs) with specific chemical groups, including SAMs-OH, SAMs-OEG, SAMs-COOH, SAMs-NH2, and SAMs-PO3H2, to study the behavior of OPN on these SAMs. The results showed that SAMs-NH2 could strongly adsorb OPN, and the amount of protein was highest on this material. Meanwhile, the lowest amount of OPN was present on SAMs-OEG. Interestingly, the unit-mass trend of bound OPN monoclonal antibodies (mAbs) on the SAMs was opposite to the OPN adsorption trend: lowest on SAMs-NH2 but highest on SAMs-OEG. In vitro cell assay results showed that mouse bone marrow mesenchymal stem cells (mBMSCs) on SAMs-COOH, SAMs-NH2, and SAMs-PO3H2 with pre-adsorbed OPN showed promoted behaviour, in terms of spreading, viability, and the expression levels of αv and β3 genes, compared with the other two SAMs, demonstrating the higher bioactivity of the adsorbed OPN. We believe that our findings will have great potential for developing OPN-activated biomaterials.
Article
Myocardial infarction (MI), which is due to cardiac dysfunction, results in morbidity and mortality. Moreover, the cellular activity of transplanted mesenchymal stem cells (MSCs)generally limits their therapeutic efficacy in the treatment of MI. Here, inject able hyaluronic acid‐chitosan/β‐glycerophosphate (HA–CS/β‐GP) hydrogel‐loaded MSCs were prepared, after which their effects on the treatment of MI were investigated. The synthesized HA–CS/β‐GP hydrogels exhibited swelling ratio (SR), an in vitro degradation value, and a gelatin time of 82.19 ± 4.1, 88.18% ± 2.4%, and 9 s, respectively. Further, rheological studies revealed that the elastic modulus of the HA–CS/β‐GP hydrogels was ≥230 Pa, exhibiting large elastic to viscous modulus ratio, which indicated their mechanical strength. Furthermore, the in vitro 3T3 cell and MSC culture studies confirmed the good biocompatibility of the HA–CS and HA–CS/β‐GP hydrogels. The implantation of the synthesized hydrogels in the mouse MI model considerably improved the therapeutic effect of the MSCs (enhanced cardiac function, reduced cardiomyocyte apoptosis, and increased vascularization) for the first time. The innovative synergistic strategy of combining injectable HA–CS and HA–CS/β‐GP hydro gels with MSCs might be suitable for the effective treatment of cardiac morbidity due to MIs. This article is protected by copyright. All rights reserved
Article
Macrophages play crucial roles in host tissue reaction to biomaterials upon implantation in vivo. However, the complexity of biomaterial degradation-related macrophage subpopulations that accumulate around the implanted biomaterials in situ is not fully understood. Here, using single cell RNA-seq, we analyze the transcriptome profiles of the various cell types around the scaffold to map the scaffold-induced reaction, in an unbiased approach. This enables mapping of all biomaterial degradation-associated cells at high resolution, revealing distinct subpopulations of tissue-resident macrophages as the major cellular sources of biomaterial degradation in situ. We also find that scaffold architecture can affect the mechanotransduction and catabolic activity of specific material degradation-related macrophage subpopulations in an Itgav-Mapk1-Stat3 dependent manner, eventually leading to differences in scaffold degradation rate in vivo. Our work dissects unanticipated aspects of the cellular and molecular basis of biomaterial degradation at the single-cell level, and provides a conceptual framework for developing functional tissue engineering scaffolds in future.
Article
Magnesium (Mg) and its alloys have emerged as a favored candidate for bio-regenerative medical implants due to their superior biocompatibility, biodegradability and the elastic modulus close to that of human bone. Unfortunately, the rapid and uncontrollable degradation rate of Mg alloys in chloride-rich body microenvironments limits their clinical orthopedic applications. Recently, Calcium Phosphate (Ca-P) biomaterials, especially Hydroxyapatite (HA), have been broadly applied in the surface functional modification of metal-based biomaterials attributed to their excellent bioactivity and biocompatibility. Hydrothermal modification of Ca-P coatings on Mg alloys has been extensively exploited by researchers for its significant superiorities in controlling coating structure and improving interfacial bonding strength for better osseointegration and corrosion resistance. This work focuses on the up-to-the-minute advances in Ca-P coatings on the surface of Mg and its alloys via hydrothermal methods, including the strategies and mechanisms of hydrothermal modification. Herein, we are inclined to share some feasible and attractive hydrothermal surface modification strategies. From the perspectives of hydrothermal manufacturing technique innovation and coating structure optimization, we evaluate how to foster the corrosion resistance, coating bonding strength, osseointegration and antibacterial properties of Mg alloys with Ca-P coatings synthesized by hydrothermal method. The challenges and future perspectives on the follow-up exploration of Mg alloys for orthopedic applications are also elaborately proposed.
Article
Full-text available
The fate of biomaterials is orchestrated by biocompatibility and bioregulation characteristics, reported to be closely related to topographical structures. For the purpose to investigate the topography of fibrous membranes on the guided bone regeneration performance, we successfully fabricated poly (lactate-co-glycolate)/fish collagen/nano-hydroxyapatite (PFCH) fibrous membranes with random, aligned and latticed topography by electrospinning. The physical, chemical and biological properties of the three topographical PFCH membranes were systematically investigated by in vitro and in vivo experiments. The subcutaneous implantation of C57BL6 mice showed an acceptable mild foreign body reaction of all three topological membranes. Interestingly, the latticed PFCH membrane exhibited superior abilities to recruit macrophage/monocyte and induce angiogenesis. We further investigated the osteogenesis of the three topographical PFCH membranes via the critical-size calvarial bone defect model of rats and mice and the results suggested that latticed PFCH membrane manifested promising performance to promote angiogenesis through upregulation of the HIF-1α signaling pathway; thereby enhancing bone regeneration. Our research illustrated that the topological structure of fibrous membranes, as one of the characteristics of biomaterials, could regulate its biological functions, and the fibrous structure of latticed topography could serve as a favorable surface design of biomaterials for bone regeneration. Statement of significance : In material-mediated regeneration medicine, the interaction between the biomaterial and the host is key to successful tissue regeneration. The micro-and nano-structure becomes one of the most critical physical clues for designing biomaterials. In this study, we fabricated three topological electrospun membranes (Random, Aligned and Latticed) to understand how topological structural clues mediate bone tissue regeneration. Interestingly, we found that the Latticed topographical PFCH membrane promotes macrophage recruitment, angiogenesis, and osteogenesis in vivo, indicating the fibrous structure of latticed topography could serve as a favorable surface design of biomaterials for bone regeneration.
Article
Full-text available
Objective: This study aimed to examine acellular extracellular matrix based hydrogels as potential therapies for treating peripheral artery disease (PAD). We tested the efficacy of using a tissue specific injectable hydrogel, derived from decellularized porcine skeletal muscle (SKM), compared to a new human umbilical cord derived matrix (hUC) hydrogel, which could have greater potential for tissue regeneration because of its young tissue source age. Background: The prevalence of PAD is increasing and can lead to critical limb ischemia (CLI) with potential limb amputation. Currently there are no therapies for PAD that effectively treat all of the underlying pathologies, including reduced tissue perfusion and muscle atrophy. Methods: In a rodent hindlimb ischemia model both hydrogels were injected 1-week post-surgery and perfusion was regularly monitored with laser speckle contrast analysis (LASCA) to 35 days post-injection. Histology and immunohistochemistry were used to assess neovascularization and muscle health. Whole transcriptome analysis was further conducted on SKM injected animals on 3 and 10 days post-injection. Results: Significant improvements in hindlimb tissue perfusion and perfusion kinetics were observed with both biomaterials. End point histology indicated this was a result of arteriogenesis, rather than angiogenesis, and that the materials were biocompatible. Skeletal muscle fiber morphology analysis indicated that the muscle treated with the tissue specific, SKM hydrogel more closely matched healthy tissue morphology. Short term histology also indicated arteriogenesis rather than angiogenesis, as well as improved recruitment of skeletal muscle progenitors. Whole transcriptome analysis indicated that the SKM hydrogel caused a shift in the inflammatory response, decreased cell death, and increased blood vessel and muscle development. Conclusion: These results show the efficacy of an injectable ECM hydrogel alone as a potential therapy for treating patients with PAD. Our results indicate that the SKM hydrogel improved functional outcomes through stimulation of arteriogenesis and muscle progenitor cell recruitment.
Article
Full-text available
Biologic scaffolds composed of naturally occurring extracellular matrix (ECM) can provide a microenvironmental niche that alters the default healing response toward a constructive and functional outcome. The present study showed similarities in the remodeling characteristics of xenogeneic ECM scaffolds when used as a surgical treatment for volumetric muscle loss in both a preclinical rodent model and five male patients. Porcine urinary bladder ECM scaffold implantation was associated with perivascular stem cell mobilization and accumulation within the site of injury, and de novo formation of skeletal muscle cells. The ECM-mediated constructive remodeling was associated with stimulus-responsive skeletal muscle in rodents and functional improvement in three of the five human patients.
Article
Full-text available
New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix as a scaffold for cardiac repair after MI. We establish the safety and efficacy of this injectable biomaterial in large- and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel 2 weeks after MI and evaluated after 3 months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.
Article
Full-text available
Surgical options for cartilage resurfacing may be significantly improved by advances and application of biomaterials that direct tissue repair. A poly(ethylene glycol) diacrylate (PEGDA) hydrogel was designed to support cartilage matrix production, with easy surgical application. A model in vitro system demonstrated deposition of cartilage-specific extracellular matrix in the hydrogel biomaterial and stimulation of adjacent cartilage tissue development by mesenchymal stem cells. For translation to the joint environment, a chondroitin sulfate adhesive was applied to covalently bond and adhere the hydrogel to cartilage and bone tissue in articular defects. After preclinical testing in a caprine model, a pilot clinical study was initiated where the biomaterials system was combined with standard microfracture surgery in 15 patients with focal cartilage defects on the medial femoral condyle. Control patients were treated with microfracture alone. Magnetic resonance imaging showed that treated patients achieved significantly higher levels of tissue fill compared to controls. Magnetic resonance spin-spin relaxation times (T(2)) showed decreasing water content and increased tissue organization over time. Treated patients had less pain compared with controls, whereas knee function [International Knee Documentation Committee (IKDC)] scores increased to similar levels between the groups over the 6 months evaluated. No major adverse events were observed over the study period. With further clinical testing, this practical biomaterials strategy has the potential to improve the treatment of articular cartilage defects.
Article
Full-text available
Autologous or synthetic vascular grafts are used routinely for providing access in hemodialysis or for arterial bypass in patients with cardiovascular disease. However, some patients either lack suitable autologous tissue or cannot receive synthetic grafts. Such patients could benefit from a vascular graft produced by tissue engineering. Here, we engineer vascular grafts using human allogeneic or canine smooth muscle cells grown on a tubular polyglycolic acid scaffold. Cellular material was removed with detergents to render the grafts nonimmunogenic. Mechanical properties of the human vascular grafts were similar to native human blood vessels, and the grafts could withstand long-term storage at 4 °C. Human engineered grafts were tested in a baboon model of arteriovenous access for hemodialysis. Canine grafts were tested in a dog model of peripheral and coronary artery bypass. Grafts demonstrated excellent patency and resisted dilatation, calcification, and intimal hyperplasia. Such tissue-engineered vascular grafts may provide a readily available option for patients without suitable autologous tissue or for those who are not candidates for synthetic grafts.
Article
Full-text available
We demonstrate here a cardiac tissue-engineering strategy addressing multicellular organization, integration into host myocardium, and directional cues to reconstruct the functional architecture of heart muscle. Microtemplating is used to shape poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel into a tissue-engineering scaffold with architectures driving heart tissue integration. The construct contains parallel channels to organize cardiomyocyte bundles, supported by micrometer-sized, spherical, interconnected pores that enhance angiogenesis while reducing scarring. Surface-modified scaffolds were seeded with human ES cell-derived cardiomyocytes and cultured in vitro. Cardiomyocytes survived and proliferated for 2 wk in scaffolds, reaching adult heart densities. Cardiac implantation of acellular scaffolds with pore diameters of 30-40 microm showed angiogenesis and reduced fibrotic response, coinciding with a shift in macrophage phenotype toward the M2 state. This work establishes a foundation for spatially controlled cardiac tissue engineering by providing discrete compartments for cardiomyocytes and stroma in a scaffold that enhances vascularization and integration while controlling the inflammatory response.
Article
Prosthetic arteriovenous grafts (AVGs) conventionally used for hemodialysis are associated with inferior primary patency rates and increased risk of infection compared with autogenous vein grafts. We tissue-engineered an AVG grown from neonatal human dermal fibroblasts entrapped in bovine fibrin gel that is then decellularized. This graft is both “off-the-shelf” (nonliving) and completely biological. Grafts that are 6 mm in diameter and about 15 cm in length were evaluated in a baboon model of hemodialysis access in an axillary-cephalic or axillary-brachial upper arm AVG construction procedure. Daily antiplatelet therapy was given. Grafts underwent both ultrasound assessment and cannulation at 1, 2, 3, and 6 months and were then explanted for analysis. Excluding grafts with cephalic vein outflow that rapidly clotted during development of the model, 3- and 6-month primary patency rates were 83% (5 of 6) and 60% (3 of 5), respectively. At explant, patent grafts were found to be extensively recellularized (including smoothelin-positive smooth muscle cells with a developing endothelium on the luminal surface). We observed no calcifications, loss of burst strength, or outflow stenosis, which are common failure modes of other graft materials. There was no overt immune response. We thus demonstrate the efficacy of an off-the-shelf AVG that is both acellular and completely biological.
Article
Decellularised mammalian extracellular matrices (ECM) have been widely accepted as an ideal substrate for repair and remodelling of numerous tissues in clinical and pre-clinical studies. Recent studies have demonstrated the ability of ECM scaffolds derived from site-specific homologous tissues to direct cell differentiation. The present study investigated the suitability of hydrogels derived from different source tissues: bone, spinal cord and dentine, as suitable carriers to deliver human apical papilla derived mesenchymal stem cells (SCAP) for spinal cord regeneration. Bone, spinal cord and dentine ECM hydrogels exhibited distinct structural, mechanical and biological characteristics. All three hydrogels supported SCAP viability and proliferation. However, only spinal cord and bone derived hydrogels promoted the expression of neural lineage markers. The specific environment of ECM scaffolds significantly affected the differentiation of SCAP to a neural lineage, with stronger responses observed with spinal cord ECM hydrogels, suggesting that site-specific tissues are more likely to facilitate optimal stem cell behaviour for constructive spinal cord regeneration. This article is protected by copyright. All rights reserved.
Article
Background: For patients with end-stage renal disease who are not candidates for fistula, dialysis access grafts are the best option for chronic haemodialysis. However, polytetrafluoroethylene arteriovenous grafts are prone to thrombosis, infection, and intimal hyperplasia at the venous anastomosis. We developed and tested a bioengineered human acellular vessel as a potential solution to these limitations in dialysis access. Methods: We did two single-arm phase 2 trials at six centres in the USA and Poland. We enrolled adults with end-stage renal disease. A novel bioengineered human acellular vessel was implanted into the arms of patients for haemodialysis access. Primary endpoints were safety (freedom from immune response or infection, aneurysm, or mechanical failure, and incidence of adverse events), and efficacy as assessed by primary, primary assisted, and secondary patencies at 6 months. All patients were followed up for at least 1 year, or had a censoring event. These trials are registered with ClinicalTrials.gov, NCT01744418 and NCT01840956. Findings: Human acellular vessels were implanted into 60 patients. Mean follow-up was 16 months (SD 7·6). One vessel became infected during 82 patient-years of follow-up. The vessels had no dilatation and rarely had post-cannulation bleeding. At 6 months, 63% (95% CI 47-72) of patients had primary patency, 73% (57-81) had primary assisted patency, and 97% (85-98) had secondary patency, with most loss of primary patency because of thrombosis. At 12 months, 28% (17-40) had primary patency, 38% (26-51) had primary assisted patency, and 89% (74-93) had secondary patency. Interpretation: Bioengineered human acellular vessels seem to provide safe and functional haemodialysis access, and warrant further study in randomised controlled trials. Funding: Humacyte and US National Institutes of Health.
Article
Engineering a healing immune response Infections, surgeries, and trauma can all cause major tissue damage. Biomaterial scaffolds, which help to guide regenerating tissue, are an exciting emerging therapeutic strategy to promote tissue repair. Sadtler et al. tested how biomaterial scaffolds interact with the immune system in damaged tissue to promote repair (see the Perspective by Badylak). Scaffolds derived from cardiac muscle and bone extracellular matrix components trigger a tissue-reparative T cell immune response in mice with injured muscles. Science , this issue p. 366 ; see also p. 298
Article
Tissue-specific elasticity arises in part from developmental changes in extracellular matrix over time, e.g. ∼ 10-fold myocardial stiffening in the chicken embryo. When this time-dependent stiffening is mimicked in vitro with thiolated hyaluronic acid (HA-SH) hydrogels, improved cardiomyocyte maturation has been observed. However, host interactions, matrix polymerization, and stiffening kinetics remain uncertain in vivo, and each plays a critical role in therapeutic applications using HA-SH. Hematological and histological analysis of subcutaneously injected HA-SH hydrogels showed minimal systemic immune response and host cell infiltration. Most importantly, subcutaneously injected HA-SH hydrogels exhibited time dependent porosity and stiffness changes at a rate similar to hydrogels polymerized in vitro. When injected intramyocardially, host cells begin to actively degrade HA-SH hydrogels within 1-week post-injection, continuing this process while producing matrix to nearly replace the hydrogel within 1 month post-injection. While non-thiolated HA did not degrade after injection into the myocardium, it also did not elicit an immune response, unlike HA-SH, where visible granulomas and macrophage infiltration were present at 1 month post-injection, likely due to reactive thiol groups. Altogether, these data suggest that the HA-SH hydrogel responds appropriately in a less vascularized niche and stiffens as had been demonstrated in vitro, but in more vascularized tissues, in vivo applicability appears limited.
Article
Myocardial infarction (MI) produces a collagen scar, altering the local microenvironment and impeding cardiac function. Cell therapy is a promising therapeutic option to replace the billions of myocytes lost following MI. Despite early successes, chronic function remains impaired and is likely a result of poor cellular retention, proliferation, and differentiation/maturation. While some efforts to deliver cells with scaffolds have attempted to address these shortcomings, they lack the natural cues required for optimal cell function. The goal of this study was to determine whether a naturally derived cardiac extracellular matrix (cECM) could enhance cardiac progenitor cell (CPC) function in vitro. CPCs were isolated via magnetic sorting of c-kit(+) cells and were grown on plates coated with either cECM or collagen I (Col). Our results show an increase in early cardiomyocyte markers on cECM compared with Col, as well as corresponding protein expression at a later time. CPCs show stronger serum-induced proliferation on cECM compared with Col, as well as increased resistance to apoptosis following serum starvation. Finally, a microfluidic adhesion assay demonstrated stronger adhesion of CPCs to cECM compared with Col. These data suggest that cECM may be optimal for CPC therapeutic delivery, as well as providing potential mechanisms to overcome the shortcomings of naked cell therapy.
Article
This study evaluated the use of an injectable hydrogel derived from ventricular extracellular matrix (ECM) for treating myocardial infarction (MI) and its ability to be delivered percutaneously. Injectable materials offer promising alternatives to treat MI. Although most of the examined materials have shown preserved or improved cardiac function in small animal models, none have been specifically designed for the heart, and few have translated to catheter delivery in large animal models. We have developed a myocardial-specific hydrogel, derived from decellularized ventricular ECM, which self-assembles when injected in vivo. Female Sprague-Dawley rats underwent ischemia reperfusion followed by injection of the hydrogel or saline 2 weeks later. The implantation response was assessed via histology and immunohistochemistry, and the potential for arrhythmogenesis was examined using programmed electrical stimulation 1 week post-injection. Cardiac function was analyzed with magnetic resonance imaging 1 week pre-injection and 4 weeks post-MI. In a porcine model, we delivered the hydrogel using the NOGA-guided MyoStar catheter (Biologics Delivery Systems, Irwindale, California), and utilized histology to assess retention of the material. We demonstrate that injection of the material in the rat MI model increases endogenous cardiomyocytes in the infarct area and maintains cardiac function without inducing arrhythmias. Furthermore, we demonstrate feasibility of transendocardial catheter injection in a porcine model. To our knowledge, this is the first in situ gelling material to be delivered via transendocardial injection in a large animal model, a critical step towards the translation of injectable materials for treating MI in humans. Our results warrant further study of this material in a large animal model of MI and suggest this may be a promising new therapy for treating MI.
Article
Soft tissue reconstruction often requires multiple surgical procedures that can result in scars and disfiguration. Facial soft tissue reconstruction represents a clinical challenge because even subtle deformities can severely affect an individual's social and psychological function. We therefore developed a biosynthetic soft tissue replacement composed of poly(ethylene glycol) (PEG) and hyaluronic acid (HA) that can be injected and photocrosslinked in situ with transdermal light exposure. Modulating the ratio of synthetic to biological polymer allowed us to tune implant elasticity and volume persistence. In a small-animal model, implanted photocrosslinked PEG-HA showed a dose-dependent relationship between increasing PEG concentration and enhanced implant volume persistence. In direct comparison with commercial HA injections, the PEG-HA implants maintained significantly greater average volumes and heights. Reversibility of the implant volume was achieved with hyaluronidase injection. Pilot clinical testing in human patients confirmed the feasibility of the transdermal photocrosslinking approach for implantation in abdomen soft tissue, although an inflammatory response was observed surrounding some of the materials.
Article
The first tissue engineered decellularized porcine heart valve, Synergraft (Cryolife Inc., USA) was introduced in Europe as an alternative to conventional biological valves. This is the first report of the rapid failure of these new grafts in a small series. In 2001, 2 model 500 and 2 model 700 Synergraft valves were implanted in four male children (age 2.5-11 years) in the right ventricular outflow tract as a root. Two patients had a Ross operation and two had a homograft replacement. The cryopreserved Synergraft valves appeared macroscopically unremarkable at implantation. Recovery from surgery was uneventful and good valve function was demonstrated postoperatively. Three children died, two suddenly with severely degenerated Synergraft valves 6 weeks and 1 year after implantation. The third child died on the 7th day due to Synergraft rupture. Subsequently the fourth graft was explanted prophylactically 2 days after implantation. Macroscopically all four grafts showed severe inflammation starting on the outside (day 2 explant) leading to structural failure (day 7 explant) and severe degeneration of the leaflets and wall (6 weeks and 1 year explant). Histology demonstrated severe foreign body type reaction dominated by neutrophil granulocytes and macrophages in the early explants and a lymphocytic reaction at 1 year. In addition significant calcific deposits were demonstrated at all stages. Surprisingly pre-implant samples of the Synergraft revealed incomplete decellularization and calcific deposits. No cell repopulation of the porcine matrix occurred. The xenogenic collagen matrix of the Synergraft valve elicits a strong inflammatory response in humans which is non-specific early on and is followed by a lymphocyte response. Structural failure or rapid degeneration of the graft occurred within 1 year. Calcific deposits before implantation and incomplete decellularization may indicate manufacturing problems. The porcine Synergraft treated heart valves should not be implanted at this stage and has been stopped.
  • B Sharma
Sharma B et al., Sci TranslMed 5, 167ra166 (2013)
  • B M Sicari
Sicari BM et al., Sci Transl Med 6, 234ra258 (2014)
  • Seif-Naraghi
  • Sb
Seif-Naraghi SB et al., Sci. Transl. Med. 5, 173ra125 (2013)
  • A Viswanath
Viswanath A et al., J. of Biomed. Mat. Res. Part A 105, 319 (2017)
  • S L Dahl
Dahl SL et al., Sci Transl Med 3, 68ra69 (2011)
  • Z H Syedain
Syedain ZH et al., Sci Transl Med 9, (2017)
  • A T Hillel
Hillel AT et al., Sci Transl Med 3, 93ra67 (2011)
  • J L Young
Young JL et al., Acta Biomater, (2013)