Nicolas L'HeureuxInserm (French National Institute of Health and Medical Research) · U1026 BioTis: Laboratory for the Bioengineering of Tissues
Nicolas L'Heureux
Ph.D.
About
65
Publications
22,766
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
6,238
Citations
Introduction
I am still a great believer in the use of biological materials to work with the body instead of trying to fool it into believing that biomaterials are not foreign. My focus remains on cell-assembled extracellular matrix (CAM) produce in culture. I am currently using yarns made from CAM. More specifically, I am looking at woven vascular grafts, but I am also looking to expand the use of these HUMAN TEXTILES into other feilds. I just need to find the right collaborators :--)
Additional affiliations
September 2015 - September 2017
Independent Researcher
Position
- Managing Director
Publications
Publications (65)
Because synthetic vascular prostheses perform poorly in small-diameter revascularization, biological vascular substitutes are being developed as an alternative. Although their in vivo results are promising, their production involves long, complex, and expensive tissue engineering methods. To overcome these limitations, we propose an innovative appr...
Background
The growing size of the end stage renal disease (ESRD) population highlights the need for effective dialysis access. Exhausted native vascular access options have led to increased use of catheters and prosthetic shunts, which are both associated with high risks of access failure and infection. Emerging alternatives include tissue-enginee...
Several tissue engineering approaches are based on the ability of mesenchymal cells to endogenously synthesize an extracellular matrix (ECM) in vitro, which can be seen as a form of biomaterial. Accordingly, the inter-donor variability of cell-assembled extracellular matrix (CAM) production is a key parameter to understand in order to progress towa...
When considering regenerative approaches, the efficient creation of a functional vasculature, that can support the metabolic needs of bioengineered tissues, is essential for their survival after implantation. However, it is widely recognized that the post-implantation microenvironment of the engineered tissues is often hypoxic due to insufficient v...
Cell-assembled extracellular matrix (CAM) has been used to produce vascular grafts. While these completely biological vascular grafts performed well in clinical trials, the in vivo remodeling and inflammatory response of this truly "bio" material has not yet been investigated. In this study, human CAM yarns were implanted sub-cutaneously in nude ra...
Thanks to its biological properties, the human amniotic membrane (HAM) combined with a bone substitute could be a single-step surgical alternative to the two-step Masquelet induced membrane (IM) technique for regeneration of critical bone defects. However, no study has directly compared these two membranes.
We first designed a 3D-printed scaffold u...
We have created entirely biological tissue-engineered vascular grafts (TEVGs) using sheets of cell-assembled extracellular matrix (CAM) produced by human fibroblasts in vitro. A large animal TEVG would allow long-term pre-clinical studies in a clinically relevant setting (graft size and allogeneic setting). Therefore, canine, porcine, ovine, and hu...
Thanks to its biological properties, the human amniotic membrane (HAM) can be used as a barrier membrane for guided bone regeneration (GBR). However, no study has assessed the influence of the preservation method of HAM for this application. This study aimed to establish the most suitable preservation method of HAM for GBR.
Fresh (F), cryopreserved...
In the field of tissue engineering, many groups have come to rely on the extracellular matrix produced by cells as the scaffold that provides structure and strength to the engineered tissue. We have previously shown that sheets of Cell-Assembled extracellular Matrix (CAM), which are entirely biological yet robust, can be mass-produced for clinical...
Because of its low immunogenicity, biological properties, and high availability, the Human Amniotic Membrane (HAM) is widely used in the clinic and in tissue engineering research. However, while its biological characteristics are well described, its mechanical properties remain understudied especially in terms of inter- and intra-HAM variability. T...
Human amniotic membrane (hAM) is considered as an attractive biological scaffold for tissue engineering. For this application, hAM has been mainly processed using cryopreservation, lyophilization and/or decellularization. However, no study has formally compared the influence of these treatments on hAM properties. The aim of this study was to develo...
We have previously shown that the Cell-Assembled extracellular Matrix (CAM) synthesized by normal, human, skin fibroblasts in vitro can be assembled in a completely biological vascular graft that was successfully tested in the clinic. The goal of this study was to perform a detailed analysis of the composition and the organization of this truly bio...
The fields of cardiovascular tissue engineering and regenerative medicine have experienced tremendous expansion and progress over the past 20 years. Strategies have focused on the use of cells, tissues, scaffolds, 3D-printing and numerous combinations of these three components to address both scientific questions and clinical needs.
Aims:
Vascular grafts made of synthetic polymers perform poorly in small-diameter applications (cardiac and peripheral bypass). Chitosan is a biocompatible natural polymer that can provide a novel biological scaffold for tissue engineering development. The goal of this study was to demonstrate the biocompatibility of a novel chitosan preparation i...
Purpose of Review
Despite an increasing list of clinically impactful products in cancer, wound care, and graft versus host disease, cellular therapeutics have yet to be fully embraced by large pharma and biotech. While there have been several high-profile investments in the past 5 years, the list of clinically and commercially successful products i...
Autografts remain the gold standard for orthopedic transplantations. However, to overcome its limitations, bone tissue engineering proposes new strategies. This includes the development of new biomaterials such as synthetic polymers, to serve as scaffold for tissue production. The objective of this present study was to produce poly(lactic) acid (PL...
Additive manufacturing covers a number of fashionable technologies that attract the interest of researchers in biomaterials and tissue engineering. Additive manufacturing applied to regenerative medicine covers two main areas: 3D printing and biofabrication. If 3D printing has penetrated the world of regenerative medicine, bioassembly and bioimprin...
An important component of critical traumatic injuries is severe limb damage. Bone repair, vascular supply integrity and wounds closure are immediate concerns but the prognosis for long-term functional recovery is largely conditioned by inadequate soft tissue regeneration, and in particular skeletal muscles. Skeletal muscles account for more than 40...
The clinical and physiological issues specific to the coronary application will be introduced, as well as current medical treatments. The evolution of tissue-engineered vascular grafts will then be summarized, followed by a discussion on the use of TESA™. Finally, novel cardiac applications for TESA™ will be discussed.
An arteriovenous fistula is the current gold standard for chronic hemodialysis access. Tunneled catheters or synthetic grafts have poorer outcomes and much higher risks of infection. This report presents the first clinical use of a completely biological, allogeneic, nonliving, and human tissue-engineered vascular graft. Tissue-engineered vascular g...
Cell-based therapies (CBTs) have been hailed for the last two decades as the next pillar of healthcare, yet the clinical and commercial potential of regenerative medicine has yet to live up to the hype. While recent analysis has suggested that regenerative medicine is maturing into a multibillion dollar industry, examples of clinical and commercial...
Clinically available transcatheter aortic valve replacement (TAVR) technologies typically use chemically fixed bovine or equine tissues for the valve leaflets. While these fixed, xenogeneic materials have been used with success in devices placed by open surgical access, the tissue thickness (>500 microns) adds significantly to the overall crossing...
Dacron® (polyethylene terephthalate) and Goretex® (expanded polytetrafluoroethylene) vascular grafts have been very successful in replacing obstructed blood vessels of large and medium diameters. However, as diameters decrease below 6 mm, these grafts are clearly outperformed by transposed autologous veins and, particularly, arteries. With approxim...
The fields of cardiovascular tissue engineering and regenerative medicine have experienced tremendous expansion and progress over the past 20 years. Strategies have focused on the use of cells, tissues, scaffolds, and numerous combinations of these three components to address both scientific questions and clinical needs.
A long-standing limitation in tissue engineering has been the dogmatic reliance on synthetic scaffolds for building tissues with significant mechanical functions despite their deleterious effects (inflammation, scarring, infection, etc.). Tissue engineering by self-assembly (TESA) is a novel approach that relies on the cell's ability to produce nat...
Since Scribner described the first prosthetic chronic dialysis shunt in 1961, the surgical techniques and strategies to maintain vascular access have improved dramatically. Today, hundreds of thousands of patients worldwide are treated with some combination of native vein fistula, synthetic vascular graft, or synthetic semipermanent catheter. Despi...
Previously we reported on the mid- to long-term follow-up in the first clinical trial to use a completely autologous tissue-engineered graft in the high pressure circulation. In these early studies, living grafts were built from autologous fibroblasts and endothelial cells obtained from small skin and vein biopsies. The graft was assembled using a...
Tissue engineering integrates knowledge and tools from biological sciences and engineering for tissue regeneration. A challenge for tissue engineering is to identify appropriate cell sources. The recent advancement of stem cell biology provides enormous opportunities to engineer stem cells for tissue engineering. The impact of stem cell technology...
A promising method to fabricate tissue-engineered blood vessels is to have cells synthesize the supportive extracellular matrix scaffold of the tissue-engineered blood vessel; however, a shortcoming of this method has been limited elastogenesis. Previously, we found that arterial smooth muscle cells (ASMCs) produced significant quantities of elasti...
Application of a tissue-engineered vascular graft for small-diameter vascular reconstruction has been a long awaited and much anticipated advance for vascular surgery. We report results after a minimum of 6 months of follow-up for the first ten patients implanted with a completely biological and autologous tissue-engineered vascular graft.
Ten pati...
We have previously reported the initial clinical feasibility with our small diameter tissue engineered blood vessel (TEBV). Here we present in vitro results of the mechanical properties of the TEBVs of the first 25 patients enrolled in an arterio-venous (A-V) shunt safety trial, and compare these properties with those of risk-matched human vein and...
Despite widespread hype and significant investment through the late 1980s and 1990s, cell-based therapeutics have largely failed from both a clinical and financial perspective. While the early pioneers were able to create clinically efficacious products, small margins coupled with small initial indications made it impossible to produce a reasonable...
Cytograft Tissue Engineering, Inc. (CA, USA) was founded in 2000 to develop a novel process, termed sheet-based tissue engineering, into a line of products aimed at meeting serious clinical needs. This platform technology differs from other tissue-engineering approaches in that it allows for the production of constructs with high mechanical strengt...
There is a considerable clinical need for alternatives to the autologous vein and artery tissues used for vascular reconstructive surgeries such as CABG, lower limb bypass, arteriovenous shunts and repair of congenital defects to the pulmonary outflow tract. So far, synthetic materials have not matched the efficacy of native tissues, particularly i...
There is a crucial need for alternatives to native vein or artery for vascular surgery. The clinical efficacy of synthetic, allogeneic or xenogeneic vessels has been limited by thrombosis, rejection, chronic inflammation and poor mechanical properties. Using adult human fibroblasts extracted from skin biopsies harvested from individuals with advanc...
Recent progress in tissue engineering led to the development of completely biological human vessels grown from the patient's own cells. Those tissue-engineered blood vessels (TEBV) are grown on an individual basis at high costs per item, and therefore require close growth monitoring and quality control. We designed and tested an optical transillumi...
Activation by C-type natriuretic peptide (CNP) of its receptor NPRB results in venodilation and inhibition of cellular proliferation. NPRB-selective antagonists should be useful to understand their physiological implications. We previously observed that [Thr9,Ser11,Arg16](N,C-ANP)pBNP (P12) is an antagonist for bNPRB and a potent agonist for bNPRA....
We have previously shown that fluid shear stress (FSS) triggers endothelial nitric oxide synthase (eNOS) activity in endothelial cells and that the mechanotransduction mechanisms responsible for activation discriminate between rapid changes in FSS and FSS per se. We hypothesized that the particular sublocalization of eNOS at the cell-cell junction...
Our method for producing tissue-engineered blood vessels based exclusively on the use of human cells, i.e., without artificial scaffolding, has previously been described (1). In this report, a tissue-engineered vascular media (TEVM) was specifically produced for pharmacological studies from cultured human vascular smooth muscle cells (VSMC). The VS...
Fluid shear stress (FSS) has been shown to be an ubiquitous stimulator of mammalian cell metabolism. Although many of the intracellular signal transduction pathways have been characterized, the primary mechanoreceptor for FSS remains unknown. One hypothesis is that the cytoplasmic membrane acts as the receptor for FSS, leading to increased membrane...
We designed a new tissue-engineered skin equivalent in which complete pilosebaceous units were integrated. This model was produced exclusively from human fibroblasts and keratinocytes and did not contain any synthetic material. Fibroblasts were cultured for 35 d with ascorbic acid and formed a thick fibrous sheet in the culture dish. The dermal equ...
For patients with extensive burns, wound coverage with an autologous in vitro reconstructed skin made of both dermis and epidermis should be the best alternative to split-thickness graft. Unfortunately, various obstacles have delayed the widespread use of composite skin substitutes. Insufficient vascularization has been proposed as the most likely...
Mechanically challenged tissue-engineered organs, such as blood vessels, traditionally relied on synthetic or modified biological materials for structural support. In this report, we present a novel approach to tissue-engineered blood vessel (TEBV) production that is based exclusively on the use of cultured human cells, i.e., without any synthetic...
Mechanically challenged tissue-engineered organs, such as blood vessels, traditionally relied on synthetic or modified biological materials for structural support. In this report, we present a novel approach to tissue-engineered blood vessel (TEBV) production that is based exclusively on the use of cultured human cells, i.e., without any synthetic...
The skin's most important function is to act as a barrier against fluid loss, microorganism infections, and percutaneous absorption. To fulfill this role, keratinocytes proliferate and differentiate to produce a protective layer: the stratum corneum. Because stem cells are responsible for the production of differentiated progeny and stem cells (K19...
Relatively limited information is available regarding the mechanisms controlling vasomotricity in human vessels. Isolated vessels obtained from patients undergoing surgery were used to characterize the role of endothelial factors and to study coupling mechanisms between receptors, intracellular calcium, and contraction. However, these investigation...
The purpose of this study was to create a tubular vascular model exclusively made of human cells and collagen.
The blood vessel equivalent was constructed with the three following human cell types: vascular smooth muscle cells, endothelial cells, and fibroblasts. A tissuelike structure was obtained from the contraction of a tubular collagen gel (hu...
Questions
Question (1)
I just changed labs and am getting my TEM done in a new place. I went to see the first samples and I see that almost all my collagen fibres are "negatively" stained. The protocol is pretty standard stuff: gluta/formaldehyde fixation, osmium post-fixation, en bloc staining with uranyl 2% (in 30% etOH), section staining with uranyl 1.5% and lead citrate. Has anyone seen this problem before?
The collagen I am staining is from the ECM of long-term cultures of fibroblasts. These samples are a little special in that the ECM was dried and kept "frozen" at -80. It was rehydrated before fixing, etc. Could this really change the way the collagen interacts with the uranyl/lead? I have a hard time believing this but I haven't stained those in TEM before and I might just be sceptical of the result because I had it done in a new place. Maybe that's "normal".
To be clear, I am not looking at the cellular components, which are completely destroyed by the drying, but at the massive extracellular deposit of collagen. Interestingly, when I look at the fibres cut longitudinal, I still see a striated aspect but when I see the cross sections, they are white. I imagine that the striation pattern is the negative of what is normally seen.
Any help would be welcome :-)
