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Contact

Dr. Nicolas L'Heureux

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Contact

Linkedin biotis-bordeaux

Secretary Email

33 (0)5 57 57 14 88

Bioingénierie Tissulaire (BioTis)       

Physical Address:

Batiment BBS (Bordeaux Biologie Santé), 5e étage

2, rue du Dr Hoffmann Martinot,

33000, Bordeaux, France

Mailing Address:

Université de Bordeaux, Campus Carreire

146, rue Léo Saignat, Case 84,

33076, Bordeaux Cedex, France

Abstract

References

Dr. Diane Potart

Project Leader

The problem:

Today’s injectable implants have limited durability, which results in patients having to undergo repeated interventions with  associated risks, suffering, and cost. Injection of implants in soft  tissue to increase volume is  used to treat  patients for a wide  range of  conditions in various medical  specialties  such  as  in:

▷[1] Haylen, B. T. et al. An International Urogynecological Association (IUGA) / International Continence Society (ICS) Joint Report on the Terminology for Female Pelvic Organ Prolapse (POP). Neurourol Urodyn 35, 137–168 (2016).

▷[2] Milsom, I. & Gyhagen, M. The prevalence of urinary incontinence. Climacteric 22, 217–222 (2019).

▷[3] Hampel, C. et al. Understanding the burden of stress urinary incontinence in Europe: A qualitative review of the literature. Eur Urol 46, 15–27 (2004).

▷[4] Brown, H. J., Zhou, D. & Husain, I. A. Management of presbyphonia: A systematic review of the efficacy of surgical intervention. American Journal of Otolaryngology - Head and Neck Medicine and Surgery 41, 102532 (2020).

▷[5] Etter, N. M. et al. Aging Voice Index (AVI): Reliability and Validity of a Voice Quality of Life Scale for Older Adults. Journal of Voice 33, 807.e7-807.e12 (2019).

▷[6] Al-Zarea, K., Sghaireen, M., Alomari, W., Bheran, H. & Taher, I. Black Triangles Causes and Management: A Review of Literature. Br J Appl Sci Technol 6, 1–7 (2015).

▷[7] Yang, T. et al. The incidence and severity of open gingival embrasures in adults treated with clear aligners and fixed appliances: a retrospective cohort study. Head Face Med 19, 1–9 (2023).

▷[8] International Society of Aesthetic Surgery. ISAPS International Survey on Aesthetic/Cosmetic Procedures in 2023. pdf (2023).

▷[9] Pavlidis, A. I. & Katsambas, A. D. Therapeutic approaches to reducing atrophic acne scarring. Clin Dermatol 35, 190–194 (2017).

▷[10] Szczerkowska-Dobosz, A., Olszewska, B., Lemańska, M., Purzycka-Bohdan, D. & Nowicki, R. Acquired facial lipoatrophy: Pathogenesis and therapeutic options. Postepy Dermatol Alergol 32, 127–133 (2015).

▷[11] Leclercq, P. et al. High prevalence and impact on the quality of life of facial lipoatrophy and other abnormalities in fat tissue distribution in HIV-infected patients treated with antiretroviral therapy. AIDS Res Hum Retroviruses 29, 761–768 (2013).

▷[12] Klopfleisch, R. & Jung, F. The pathology of the foreign body reaction against biomaterials. J Biomed Mater Res A (2017) doi:10.1002/jbm.a.35958.

▷[13] Lemperle, G. et al. Foreign body granulomas after all injectable dermal fillers: Part 1. possible causes. Plast Reconstr Surg 123, 1842–1863 (2009).

▷[14] L’Heureux, N., McAllister, T. N. & De La Fuente, L. M. Tissue-engineered blood vessel for adult arterial revascularization. The New England Journal of Medecine 357, 1451–1453 (2007).

▷[15] McAllister, T. N. et al. Effectiveness of haemodialysis access with an autologous tissue-engineered vascular graft: a multicentre cohort study. The Lancet 373, 1440–1446 (2009).

▷[16] Wystrychowski, W. et al. Long-term results of autologous scaffold-free tissue-engineered vascular graft for haemodialysis access (in press). Journal of Vascular Access (2022).

▷[17] Wystrychowski, W. et al. First human use of an allogeneic tissue-engineered vascular graft for hemodialysis access. J Vasc Surg 60, 1353–1357 (2014).

▷[18] Magnan, L. et al. In vivo remodeling of human cell-assembled extracellular matrix yarns. Biomaterials 273, (2021).

▷[19] Kawecki, F. et al. Inter-donor variability of extracellular matrix production in long-term cultures of human fibroblasts. Biomater Sci 10, 3935–3950 (2022).

▷[20] Wystrychowski, W. et al. First human use of an allogeneic tissue-engineered vascular graft for hemodialysis access. J Vasc Surg 60, 1353–1357 (2014).

▷[21] L’Heureux, N. et al. Human tissue-engineered blood vessels for adult arterial revascularization. Nat Med 12, 361–365 (2006).

▷[22] Potart, D. et al. The Cell-Assembled extracellular Matrix: a focus on the storage stability and terminal sterilization of this human ‘bio’ material. Acta Biomater 166, 133–146 (2023).


Dr. Yoann Torres

Collaborator

by the host to fit its needs, rather than as a foreign body that needs to be destroyed (Figure 1). This is because the CAM is human and completely biological and, more importantly, because the ultrastructure of the extracellular matrix (ECM) created by the cells was not denatured by physicochemical treatments. We have shown that the CAM will not trigger rapid degradation, unlike processed/denatured ECM-based commercially available implants[18]. Although it will be allogenic in our ultimate clinical strategy, the human nature of the CAM will avoid rejection by the adaptive immune system because all members of the same species have the same ECM molecules[17,19]. In addition, we have shown that the allogenic cellular remnants do not create significant reactivity[20]. For these reasons, and based on human[15-17],[21] and animal18, we believe that the CAM will be recolonized by host cells to become an actual living tissue, and only  a  very  slow  turnover  of  the ECM  (physiological rate)  will take place .

The solution:

We propose a new paradigm that relies on the use of a completely biological, non-living, and human material produced in the laboratory that has tissue-like ultrastructure. Our strategy is based on the use of Cell-Assembled extracellular Matrix (CAM) sheets produced by normal, adult human fibroblasts in vitro. The sheets can then be cut into very small sheets (i.e., microsheets) or into thin ribbons that can be injected. We believe that this minimally manipulated bio-material will provide unparalleled durability, and thus efficacy, in increasing tissue volume. Previously, CAM sheets were rolled to produce small-diameter blood vessels that have been tested in a clinical trial with very promising results of up to 3 years[14-16] even when using allogenic fibroblasts to produce the CAM [17] . The CAM is recognized as a biological tissue  that can be remodeled by the host to fit its  needs, rather than as  a

The fundamental problem with the injectable implants used in the applications mentioned above is that they are all recognized as foreign body by the innate immune system of the patient, which will generate the well-characterized “foreign body reaction”(FBR), for review see [12]. In most cases, this reaction leads to the degradation of the implanted products, which eventually lose their volume and no longer fulfill their filling or bulking function. In the worst- case scenarios, this reaction leads to a chronic inflammatory state, leading to complications such as chronic pain, granuloma formation, tissue erosion, and infections[13]. Therefore, there  is a  widespread clinical need for  new and  innovative solutions that are longer-lasting and safer.

Cécile Monfoulet

Dr. Audrey Aussel

• The urogenital field, for the treatment of stress urinary incontinence (SUI - involuntary leakage of urine during physical activities[1], 1 in 5 women[2,3]).

• The oto-rhino-laryngology field, for the treatment of presbyphonia (voice disorders, 30% of people over 60 years old[4,5]).

• The dental surgery field, for the treatment of open gingival embrasure (incomplete filling of the space between teeth, 67% of people over 20 years old[6,7]).

• The plastic surgery field, to compensate for volume loss due to skin aging (wrinkles and skin folds, more than 5 million injections/year worldwide[8]), acne (atrophic scars, 1 in 10 people[9]) or HIV (fascial lipoatrophy, 1 in  2 HIV patient treated with long-term  antiretroviral  therapy[10,11]).

This is truly a new paradigm because we provide a matrix to support new biological and living tissue formation by the host, instead of “fighting the body” by implanting synthetic or denatured agents. This tissue-engineered, non-living, human implant is a next-generation product that will provide tissue volume stability and avoid chronic inflammation, which will improve the quality of life of patients by avoiding repeated  procedures and serious  complications.

Injectable CAM formulation to rebuild tissue

Persefoni Lykourgioti

Figure 1: Histological sections (HE stain) of implants after 1 month in immunodeficient rats. (A) CAM ribbon is slowly remodeled (barely no inflammation)[22]. (B) Nylon suture triggers chronic inflammation with markers of the FBR, i.e., giant cells (*)(unpublished data).