Translating Ideas into Commercial Biomaterial Devices: A Path to Improving Healthcare.

The medical device industry is undergoing substantial transformations, looking to face the increasing pressures on healthcare systems and fundamental shifts in healthcare delivery. There is an ever-growing emphasis on identifying underserved clinical requirements and enhancing industry-academia partnerships to accelerate innovative solutions. In this context, an analysis of the requirements for translation, highlighting support and funding for innovation to transform an idea for a biomaterial device into a commercially available product, is discussed.

A novel self-gripping long-term resorbable mesh providing temporary support for open primary ventral and incisional hernia.

A novel synthetic fully long-term resorbable self-gripping mesh has been recently developed to reinforce soft tissue where weakness exists during ventral hernia repair open procedures. This resorbable mesh is a macroporous, knitted, poly-L-lactide, poly-trimethylene carbonate copolymer monofilament mesh with the ProGrip™ technology, providing grips on one side of the mesh. A new poly-L-lactide, poly-trimethylene copolymer was developed to provide the required features for mechanical support during at least 20 weeks covering the critical healing period, including resistance to fatigue under cyclic loading conditions, as it occurs in patients. The yarns and mesh initial physical and biomechanical properties were characterized. Then, the mesh mechanical strength was evaluated over time. The mechanical properties of the proposed mesh were found to be above the generally recognized threshold value to mechanically support the repair site of a hernia over a 20-week period during in-vitro cyclic loading test. The mesh performance was evaluated in vivo using a published preclinical porcine model of hernia repair at 4-, 12- and 20-weeks post implantation. The burst strength of the hernia repair sites reinforced with the new mesh were higher at 4 & 12 weeks and comparable at 20 weeks to the one of the native abdominal walls. At all time points, the mesh was well tolerated with moderate inflammation and was fast integrated in the abdominal wall at 4 weeks. Particularly, the grips were nicely engulfed in the newly formed connective tissue. They must facilitate the anchoring of the mesh by their extension from the mesh and their mushroom shape. The preclinical data of the self-gripping resorbable mesh suggests that it has all the favorable characteristics for future clinical use during ventral hernia repair open procedures.

Development of three-layer collagen scaffolds to spatially direct tissue-specific cell differentiation for enthesis repair.

Enthesis repair remains a challenging clinical indication. Herein, a three-layer scaffold composed of a tendon-like layer of collagen type I, a fibrocartilage-like layer of collagen type II and a bone-like layer of collagen type I and hydroxyapatite, was designed to recapitulate the matrix composition of the enthesis. To aid tenogenic and fibrochondrogenic differentiation, bioactive molecules were loaded in the tendon-like layer or the fibrocartilage-like layer and their effect was assessed in in vitro setting using human bone marrow derived mesenchymal stromal cells and in an ex vivo model. Seeded human bone marrow mesenchymal stromal cells infiltrated and homogeneously spread throughout the scaffold. As a response to the composition of the scaffold, cells differentiated in a localised manner towards the osteogenic lineage and, in combination with differentiation medium, towards the fibrocartilage lineage. Whilst functionalisation of the tendon-like layer did not improve tenogenic cell commitment within the time frame of this work, relevant fibrochondrogenic markers were detected in the fibrocartilage-like layer when scaffolds were functionalised with bone morphogenetic protein 2 or non-functionalised at all, in vitro and ex vivo, respectively. Altogether, our data advocate the use of compartmentalised scaffolds for the repair and regeneration of interfacial tissues, such as enthesis.

Monocyte response after colorectal surgery: A prospective cohort study.

Background: Tumor resection is the common approach in patients with colorectal malignancy. Profound insight into inflammatory changes that accompany the normal post-operative stress response will establish reference parameters useful for identification of putative complications. Alterations in circulating monocytes might be indicative as these cells are considered to be the most responsive leukocytes to trauma. Therefore, the aim of this study is to assess the monocyte subset kinetic and phenotypic changes in response to surgery. Methods: Fifty patients undergoing colorectal tumor resection were included in a multicenter prospective cohort study. Blood samples were collected early in the morning prior to surgery and the next days through postoperative day three for flowcytometric analysis. Leukocyte subtypes were identified and expression of activation stage-related markers by monocyte subsets was quantified. Results: Changes in leukocyte subset composition and monocyte subset phenotypes were most prominent at the first day postoperatively, after which these parameters typically returned to normal or near-normal preoperative values. The immunophenotypic alterations after surgery were most notable in classical and intermediate monocytes. These included up-regulation of activation markers CD64 and CD62L, but down-regulation of HLA-DR and CD54. Markers of de-activation, CD163 and CD206, were consistently increasingly expressed. Discussion/conclusion: The current study gives detailed insight into the peripheral blood leukocyte response after colorectal cancer surgery. This form of short-term stress induces a rapid and significant redistribution of immune cells. Immunophenotypic alterations in monocytes as a response to surgery suggest a mixed profile of cellular activation and de-activation.

Assessing the combined effect of surface topography and substrate rigidity in human bone marrow stem cell cultures.

The combined effect of surface topography and substrate rigidity in stem cell cultures is still under-investigated, especially when biodegradable polymers are used. Herein, we assessed human bone marrow stem cell response on aliphatic polyester substrates as a function of anisotropic grooved topography and rigidity (7 and 12 kPa). Planar tissue culture plastic (TCP, 3 GPa) and aliphatic polyester substrates were used as controls. Cell morphology analysis revealed that grooved substrates caused nuclei orientation/alignment in the direction of the grooves. After 21 days in osteogenic and chondrogenic media, the 3 GPa TCP and the grooved 12 kPa substrate induced significantly higher calcium deposition and alkaline phosphatase (ALP) activity and glycosaminoglycan (GAG) deposition, respectively, than the other groups. After 14 days in tenogenic media, the 3 GPa TCP upregulated four and downregulated four genes; the planar 7 kPa substrate upregulated seven genes and downregulated one gene; and the grooved 12 kPa substrate upregulated seven genes and downregulated one gene. After 21 days in adipogenic media, the softest (7 kPa) substrates induced significantly higher oil droplet deposition than the other substrates and the grooved substrate induced significantly higher droplet deposition than the planar. Our data pave the way for more rational design of bioinspired constructs.

Development of a Connected Sensor System in Colorectal Surgery: User-Centered Design Case Study.

BACKGROUND: A successful innovative medical device is not only technically challenging to develop but must also be readily usable to be integrated into health care professionals' daily practice. Through a user-centered design (UCD) approach, usability can be improved. However, this type of approach is not widely implemented from the early stages of medical device development. OBJECTIVE: The case study presented here shows how UCD may be applied at the very early stage of the design of a disruptive medical device used in a complex hospital environment, while no functional device is available yet. The device under study is a connected sensor system to detect colorectal anastomotic leakage, the most detrimental complication following colorectal surgery, which has a high medical cost. We also aimed to provide usability guidelines for the initial design of other innovative medical devices. METHODS: UCD was implemented by actively involving health care professionals and all the industrial partners of the project. The methodology was conducted in 2 European hospitals: Grenoble-Alpes University Hospital (France) and Erasmus Medical Center Rotterdam (the Netherlands). A total of 6 elective colorectal procedures and 5 ward shifts were observed. In total, 4 workshops were conducted with project partners and clinicians. A formative evaluation was performed based on 5 usability tests using nonfunctional prototype systems. The case study was completed within 12 months. RESULTS: Functional specifications were defined for the various components of the medical device: device weight, size, design, device attachment, and display module. These specifications consider the future integration of the medical device into current clinical practice (for use in an operating room and patient follow-up inside the hospital) and interactions between surgeons, nurses, nurse assistants, and patients. By avoiding irrelevant technical development, this approach helps to promote cost-effective design. CONCLUSIONS: This paper presents the successful deployment over 12 months of a UCD methodology for the design of an innovative medical device during its early development phase. To help in reusing this methodology to design other innovative medical devices, we suggested best practices based on this case.

Incidence and risk factors for incisional hernia and recurrence: Retrospective analysis of the French national database.

AIM: The aim of this work was to determine the rate of incisional hernia (IH) repair and risk factors for IH repair after laparotomy. METHOD: This population-based study used data extracted from the French Programme de Médicalisation des Systèmes d'Informations (PMSI) database. All patients who had undergone a laparotomy in 2010, their hospital visits from 2010 to 2015 and patients who underwent a first IH repair in 2013 were included. Previously identified risk factors included age, gender, high blood pressure (HBP), obesity, diabetes and chronic obstructive pulmonary disease (COPD). RESULTS: Among the 431 619 patients who underwent a laparotomy in 2010, 5% underwent IH repair between 2010 and 2015. A high-risk list of the most frequent surgical procedures (>100) with a significant risk of IH repair (>10% at 5 years) was established and included 71 863 patients (17%; 65 procedures). The overall IH repair rate from this list was 17%. Gastrointestinal (GI) surgery represented 89% of procedures, with the majority of patients (72%) undergoing lower GI tract surgery. The IH repair rate was 56% at 1 year and 79% at 2 years. Risk factors for IH repair included obesity (31% vs 15% without obesity, p  < 0.001), COPD (20% vs 16% without COPD), HBP (19% vs 15% without HBP) and diabetes (19% vs 16% without diabetes). Obesity was the main risk factor for recurrence after IH repair (19% vs 13%, p < 0.001). CONCLUSION: From the PMSI database, the real rate of IH repair after laparotomy was 5%, increasing to 17% after digestive surgery. Obesity was the main risk factor, with an IH repair rate of 31% after digestive surgery. Because of the important medico-economic consequences, prevention of IH after laparotomy in high-risk patients should be considered.

Enabling MedTech Translation in Academia: Redefining Value Proposition with Updated Regulations.

Academic institutions are becoming more focused on translating new technologies for clinical applications. A transition from "bench to bedside" is often described to take basic research concepts and methods to develop a therapeutic or diagnostic solution with proven evidence of efficacy at the clinical level while also fulfilling regulatory requirements. The regulatory environment is evolving in Europe with transition and grace periods for the full enforcement of the Medical Device Regulation 2017/745 (MDR), replacing the Medical Device Directive 93/42/EEC (MDD). These new guidelines increase demands for scientific, technical, and clinical data with reduced capacity in regulatory bodies creating uncertainty in future product certification. Academic translational activities will be uniquely affected by this new legislation. The barriers and threats to successful translation in academia can be overcome by strong clinical partnerships, close-industrial collaborations, and entrepreneurial programs, enabling continued product development to overcome regulatory hurdles, reassuring their foothold of medical device development.

Development and characterisation of cytocompatible polyester substrates with tunable mechanical properties and degradation rate.

Although it has been repeatedly indicated the importance to develop implantable devices and cell culture substrates with tissue-specific rigidity, current commercially available products, in particular cell culture substrates, have rigidity values well above most tissues in the body. Herein, six resorbable polyester films were fabricated using compression moulding with a thermal presser into films with tailored stiffness by appropriately selecting the ratio of their building up monomers (e.g. lactide, glycolide, trimethylene carbonate, dioxanone, ε-caprolactone). Typical NMR and FTIR spectra were obtained, suggesting that the fabrication process did not have a negative effect on the conformation of the polymers. Surface roughness analysis revealed no apparent differences between the films as a function of polymer composition. Subject to polymer composition, polymeric films were obtained with glass transition temperatures from -52 °C to 61 °C; contact angles in water from 81 ° to 94 °; storage modulus from 108 MPa to 2,756 MPa and loss modulus from 8 MPa to 507 MPa (both in wet state, at 1 Hz frequency and at 37 °C); ultimate tensile strength from 8 MPa to 62 MPa, toughness from 23 MJ/m3 to 287 MJ/m3, strain at break from 3 % to 278 %, macro-scale Young's modulus from 110 MPa to 2,184 MPa (all in wet state); and nano-scale Young's modulus from 6 kPa to 15,019 kPa (in wet state). With respect to in vitro degradation in phosphate buffered saline at 37 °C, some polymeric films [e.g. poly(glycolide-lactide) 30 / 70] started degrading from day 7 (shortest timepoint assessed), whilst others [e.g. poly(glycolide-co-ε-caprolactone) 10 / 90] were more resilient to degradation up to day 21 (longest timepoint assessed). In vitro biological analysis using human dermal fibroblasts and a human monocyte cell line (THP-1) showed the potential of the polymeric films to support cell growth and controlled immune response. Evidently, the selected polymers exhibited properties suitable for a range of clinical indications.

The Few Who Made It: Commercially and Clinically Successful Innovative Bone Grafts.

Bone reconstruction techniques are mainly based on the use of tissue grafts and artificial scaffolds. The former presents well-known limitations, such as restricted graft availability and donor site morbidity, while the latter commonly results in poor graft integration and fixation in the bone, which leads to the unbalanced distribution of loads, impaired bone formation, increased pain perception, and risk of fracture, ultimately leading to recurrent surgeries. In the past decade, research efforts have been focused on the development of innovative bone substitutes that not only provide immediate mechanical support, but also ensure appropriate graft anchoring by, for example, promoting de novo bone tissue formation. From the countless studies that aimed in this direction, only few have made the big jump from the benchtop to the bedside, whilst most have perished along the challenging path of clinical translation. Herein, we describe some clinically successful cases of bone device development, including biological glues, stem cell-seeded scaffolds, and gene-functionalized bone substitutes. We also discuss the ventures that these technologies went through, the hindrances they faced and the common grounds among them, which might have been key for their success. The ultimate objective of this perspective article is to highlight the important aspects of the clinical translation of an innovative idea in the field of bone grafting, with the aim of commercially and clinically informing new research approaches in the sector.

Automation, Monitoring, and Standardization of Cell Product Manufacturing.

Although regenerative medicine products are at the forefront of scientific research, technological innovation, and clinical translation, their reproducibility and large-scale production are compromised by automation, monitoring, and standardization issues. To overcome these limitations, new technologies at software (e.g., algorithms and artificial intelligence models, combined with imaging software and machine learning techniques) and hardware (e.g., automated liquid handling, automated cell expansion bioreactor systems, automated colony-forming unit counting and characterization units, and scalable cell culture plates) level are under intense investigation. Automation, monitoring and standardization should be considered at the early stages of the developmental cycle of cell products to deliver more robust and effective therapies and treatment plans to the bedside, reducing healthcare expenditure and improving services and patient care.

The effect of aligned electrospun fibers and macromolecular crowding in tenocyte culture.

Tendon injuries continuously rise, and regeneration is not only slow, but also limited due to the poor endogenous healing ability of the tendon tissue. Tissue grafts constitute the clinical gold standard treatment for severe injuries, but inherent limitations drive the field toward tissue engineering approaches to create suitable tissue constructs. Recapitulation of the native microenvironment represent a key challenge for the development of tendon tissue equivalents in vitro that can be further utilized as implantable devices. Methods to maintain cellular phenotype and to enhance extracellular matrix deposition for accelerated development of tissue-like modulus should be developed. Herein, we assessed the combining effect of surface topography and macromolecular crowding in human tenocyte culture. Our data demonstrated that bidirectionally aligned electrospun fibers induce physiological cell growth, while macromolecular crowding enhanced and accelerated tissue-specific extracellular matrix deposition. Collectively, these data advocate the use of multifactorial approaches for the accelerated development of functional tissue-like surrogates in vitro.

Translational Research Symposium-collaborative efforts as driving forces of healthcare innovation.

The 5th Translational Research Symposium was organised at the annual meeting of the European Society for Biomaterials 2018, Maastricht, the Netherlands, with emphasis on the future of emerging and smart technologies for healthcare in Europe. Invited speakers from academia and industry highlighted the vision and expectations of healthcare in Europe beyond 2020 and the perspectives of innovation stakeholders, such as small and medium enterprises, large companies and Universities. The aim of the present article is to summarise and explain the main statements made during the symposium, with particular attention on the need to identify unmet clinical needs and their efficient translation into healthcare solutions through active collaborations between all the participants involved in the value chain.

Cellular and collagen reference values of gingival and periodontal ligament tissues in rats: a pilot study.

Reference data are lacking on the periodontal ligament and the gingival tissue of the rat model, which would be useful for studies of new medical or biomaterial periodontal treatments. The objective of the current study was to propose cellular and collagen reference values of gingival and periodontal ligament tissues in rat, using a simple and reliable quantitative method after decalcification. Mandibular samples of ten adult Sprague-Dawley rats were used. Mild decalcification was carried out using ethylenediaminetetraacetic acid (EDTA) to preserve the morphology of tissues. Half of the samples were decalcified and the other half were not. The gingiva and the periodontal ligament were analyzed. Descriptive histology and computer-assisted image analysis were performed. The data showed that qualitatively, cellular and extracellular matrix morphologies were well preserved compared to non-decalcified periodontal soft tissue biopsies. Histomorphometrically, constitutive cellularity and the total amount of native collagen, collagen directionality and collagen anisotropy in both experimental conditions did not significantly differ. Taken together, these results suggested that EDTA decalcification did not negatively affect the studied endpoints. Moreover, this mild decalcification method allowed in situ maintenance of the periodontal soft and hard tissue integrity. The structural and compositional computerized assessment performed in the healthy periodontal soft tissue could provide reference values that will be required for future assessment on the effects of pathological, reparative and regenerative processes in rat periodontal soft tissues.

Resorbable Synthetic Meshes for Abdominal Wall Defects in Preclinical Setting: A Literature Review.

BACKGROUND: Prosthetic materials for the repair of abdominal wall defects have been studied extensively to improve outcome. A new approach can be the use of a slowly resorbable synthetic mesh, which aims to combine advantages of both synthetic and biological meshes. The objective of this review is to give an overview of the physicochemical characteristics and biomechanical, histological, and macroscopic outcome (recurrence, adhesion formation) of the use of resorbable synthetic meshes, for treatment and prevention of abdominal wall hernias, based on experimental studies. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only experimental studies were included. Outcome parameters were resorption, degradation, organization of connective tissue, inflammatory response, tensile strength, and amount of adhesion formation. Surgical characteristics were taken into account as well (type of defect, clean versus contaminated model, position mesh, repair of the defect, recurrences). RESULTS: In total, eleven articles were included. Three absorbable synthetic meshes are currently available: GORE BIO-A mesh (Gore), TIGR Matrix Surgical mesh (Novus Scientific), and Phasix mesh (Bard). Two studies concluded that, despite an early transient inflammatory reaction in the first months, remodeling was good in GORE BIO-A, 6-12 mo after augmentation or suture line reinforcement with only minimal to moderate adhesions when used intraperitoneally. The TIGR Matrix Surgical mesh shows only partial remodeling with a persistent foreign body reaction after 1 y. Phasix mesh seems to perform well in extraperitoneal implantation after 1 y in two studies, although the defect was small. Only two studies directly compared two resorbable synthetic meshes under the same circumstances. The latter also included a number of animals where the meshes were used in a contaminated nonhernia model. No hernia recurrences or deaths of animals were described in all studies. CONCLUSIONS: The use of resorbable synthetic meshes in the prevention or treatment of abdominal wall defects in animal experiments with small defects in clean setting seems safe, with no serious complications related to the device during short-term follow-up. However, there is no evidence available that can support the advantages of resorbable synthetic meshes over the use of synthetic or biological meshes, mostly due to lack of good data. More experimental studies are needed, followed by randomized controlled trials and prospective registries in humans with a sufficiently long follow-up period, to reveal the potential advantages in clinical practice.

The Collagen Suprafamily: From Biosynthesis to Advanced Biomaterial Development.

Collagen is the oldest and most abundant extracellular matrix protein that has found many applications in food, cosmetic, pharmaceutical, and biomedical industries. First, an overview of the family of collagens and their respective structures, conformation, and biosynthesis is provided. The advances and shortfalls of various collagen preparations (e.g., mammalian/marine extracted collagen, cell-produced collagens, recombinant collagens, and collagen-like peptides) and crosslinking technologies (e.g., chemical, physical, and biological) are then critically discussed. Subsequently, an array of structural, thermal, mechanical, biochemical, and biological assays is examined, which are developed to analyze and characterize collagenous structures. Lastly, a comprehensive review is provided on how advances in engineering, chemistry, and biology have enabled the development of bioactive, 3D structures (e.g., tissue grafts, biomaterials, cell-assembled tissue equivalents) that closely imitate native supramolecular assemblies and have the capacity to deliver in a localized and sustained manner viable cell populations and/or bioactive/therapeutic molecules. Clearly, collagens have a long history in both evolution and biotechnology and continue to offer both challenges and exciting opportunities in regenerative medicine as nature's biomaterial of choice.

Recent Progress in European Advanced Therapy Medicinal Products and Beyond.

Cell- and gene-based therapies form one of the pillars of regenerative medicine. They have the potential to transform quality of life and improve the health status of patients with genetic and cellular defects, including genetic diseases, neurodegenerative diseases and tissue malignancies, amongst others. Despite numerous challenges, in the last decade, tremendous unified efforts by research and clinical scientists in academic, translational and industry settings have resulted in tangible outcomes in the form of many marketing authorizations and approved commercial firsts, such as Glybera®, Kymriah®, YESCARTA®, Holoclar®, and Luxturna™. This report presents a succinct analysis of developments in the regenerative medicine landscape, including immuno-oncology, with a focus on the European Union and examples of clinical and commercial successes and failures. The factors that led to these exciting developments in immune-oncology are also considered. Concurrently, several key issues, spanning from the identification of unmet clinical need, associated challenges, economic evaluation to policy improvements are emphasized. Furthermore, industry insights encompassing the five-dimensional research and development framework for the focused development of medicine, pricing and reimbursement issues, technology adoption and permeation of innovative advanced therapy medicinal products in the clinical set up are reflected upon, following elaborate discussions that transpired in different thematic tracks of Tissue Engineering & Regenerative Medicine International Society European Chapter 2017 Industry Symposium.

Joint academic and industrial efforts towards innovative and efficient solutions for clinical needs.

The 4th Translational Research Symposium (TRS) was organised at the annual meeting of the European Society for Biomaterials (ESB) 2017, Athens, Greece, with a focus on 'Academia-Industry Clusters of Research for Innovation Catalysis'. Collaborations between research institutes and industry can be sustained in several ways such as: European Union (EU) funded consortiums; syndicates of academic institutes, clinicians and industries; funding from national governments; and private collaborations between universities and companies. Invited speakers from industry and research institutions presented examples of these collaborations in the translation of research ideas or concepts into marketable products. The aim of the present article is to summarize the key messages conveyed during these lectures. In particular, emphasis is put on the challenges to appropriately identify and select unmet clinical needs and their translation by ultimately implementing innovative and efficient solutions achieved through joint academic and industrial efforts.

Devising tissue ingrowth metrics: a contribution to the computational characterization of engineered soft tissue healing.

The paradigm shift brought about by the expansion of tissue engineering and regenerative medicine away from the use of biomaterials, currently questions the value of histopathologic methods in the evaluation of biological changes. To date, the available tools of evaluation are not fully consistent and satisfactory for these advanced therapies. We have developed a new, simple and inexpensive quantitative digital approach that provides key metrics for structural and compositional characterization of the regenerated tissues. For example, metrics provide the tissue ingrowth rate (TIR) which integrates two separate indicators; the cell ingrowth rate (CIR) and the total collagen content (TCC) as featured in the equation, TIR% = CIR% + TCC%. Moreover a subset of quantitative indicators describing the directional organization of the collagen (relating structure and mechanical function of tissues), the ratio of collagen I to collagen III (remodeling quality) and the optical anisotropy property of the collagen (maturity indicator) was automatically assessed as well. Using an image analyzer, all metrics were extracted from only two serial sections stained with either Feulgen & Rossenbeck (cell specific) or Picrosirius Red F3BA (collagen specific). To validate this new procedure, three-dimensional (3D) scaffolds were intraperitoneally implanted in healthy and in diabetic rats. It was hypothesized that quantitatively, the healing tissue would be significantly delayed and of poor quality in diabetic rats in comparison to healthy rats. In addition, a chemically modified 3D scaffold was similarly implanted in a third group of healthy rats with the assumption that modulation of the ingrown tissue would be quantitatively present in comparison to the 3D scaffold-healthy group. After 21 days of implantation, both hypotheses were verified by use of this novel computerized approach. When the two methods were run in parallel, the quantitative results revealed fine details and differences not detected by the semi-quantitative assessment, demonstrating the importance of quantitative analysis in the performance evaluation of soft tissue healing. This automated and supervised method reduced operator dependency and proved to be simple, sensitive, cost-effective and time-effective. It supports objective therapeutic comparisons and helps to elucidate regeneration and the dynamics of a functional tissue.