The value of organ and tissue biovigilance: a cross-sectional analysis.

Introduction: Biovigilance (BV) systems aim to improve the quality and safety of tissues and organs for transplantation. This study describes the Catalan BV system and analyzes its utility. Methods: It is a retrospective analysis of notifications on serious adverse events (SAEs) and reactions (SARs) since the implementation of the BV system (2008 for tissues and 2016 for organs) until 2020. Variables are presented to describe the most common critical steps of the pathway and complications associated with the quality and safety of tissues and organs. Results: A total of 154 and 125 notifications were reported to the Tissue and the Organ BV systems, respectively. Most SAEs were related to unexpected donor diseases and implemented actions were assured on those deemed preventable. Regarding SARs, donor-transmitted infections and malignancies (only organs) were the most common, followed by graft failure (tissues) and process-related (organs). The incidence of SAEs and SARs related to tissue was 3.44‰ and 0.22‰, respectively. The corresponding figures for organs were 31.48‰ and 8.8‰, respectively. Discussion: The analysis of the notifications to the Catalan BV systems has provided useful information about existing risks associated with the quality and safety of tissues and organs, and enabled the implementation of actions targeted to diminish risks and mitigate damage.

BeST-Graft viewer, a new system to improve the bone allograft-recipient matching process.

INTRODUCTION: Tissue establishments are responsible for processing, testing, preserving, storing, and distributing allografts from donors to be transplanted into recipients. In some situations, a matching process is required to determine the allograft that best fits the recipient. Allograft morphology is a key consideration for the matching process. The manual procedures applied to obtain these parameters make the process error-prone. MATERIAL AND METHODS: A new system to manage bone allograft-recipient matching for tissue establishments is proposed. The system requires bone allografts to be digitalized and the resulting images to be stored in a DICOM file. The system provides functionalities to: (i) manage DICOM files (registered in the PACs) from both allografts and recipients; (ii) reconstruct 3D models from DICOM images; (iii) explore 3D models using 2D, 3D, and multiplanar reconstructions; (iv) take allograft and recipient measurements; and (v) visualize and interact with recipient and allograft data simultaneously. The system has been installed in the Barcelona Tissue Bank (Banc de Sang i Teixits), which has digitalized the bone allografts to test the system. RESULTS: A use case with a femur is presented to test all the viewer functionalities. In addition, the recipient-allograft workflow is evaluated to show the steps of the procedure where the viewer can be used. CONCLUSIONS: The bone allograft-recipient matching procedure can be optimized using software tools with functionalities to visualize, interact, and take measurements.

Implantation of a double allogeneic human engineered tissue graft on damaged heart: insights from the PERISCOPE phase I clinical trial.

BACKGROUND: In preclinical studies, the use of double allogeneic grafts has shown promising results in promoting tissue revascularization, reducing infarct size, preventing adverse remodelling and fibrosis, and ultimately enhancing cardiac function. Building upon these findings, the safety of PeriCord, an engineered tissue graft consisting of a decellularised pericardial matrix and umbilical cord Wharton's jelly mesenchymal stromal cells, was evaluated in the PERISCOPE Phase I clinical trial (NCT03798353), marking its first application in human subjects. METHODS: This was a double-blind, single-centre trial that enrolled patients with non-acute myocardial infarction eligible for surgical revascularization. Seven patients were implanted with PeriCord while five served as controls. FINDINGS: Patients who received PeriCord showed no adverse effects during post-operative phase and one-year follow-up. No significant changes in secondary outcomes, such as quality of life or cardiac function, were found in patients who received PeriCord. However, PeriCord did modulate the kinetics of circulating monocytes involved in post-infarction myocardial repair towards non-classical inflammation-resolving macrophages, as well as levels of monocyte chemoattractants and the prognostic marker Meteorin-like in plasma following treatment. INTERPRETATION: In summary, the PeriCord graft has exhibited a safe profile and notable immunomodulatory properties. Nevertheless, further research is required to fully unlock its potential as a platform for managing inflammatory-related pathologies. FUNDING: This work was supported in part by grants from MICINN (SAF2017-84324-C2-1-R); Instituto de Salud Carlos III (ICI19/00039 and Red RICORS-TERAV RD21/0017/0022, and CIBER Cardiovascular CB16/11/00403) as a part of the Plan Nacional de I + D + I, and co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR (2021-SGR-01437).

Quality by Design: Development of Safe and Efficacious Full-Thickness Acellular Dermal Matrix Based on EuroGTPII Methodologies.

Background: The activities of tissue establishments are constantly and rapidly evolving. The development of a new type of allograft, full-thickness acellular dermal matrix, with high mechanical properties to be used in tendon repair surgeries and abdominal wall reconstruction, has determined the need for quality by design process in order to assess evidence of quality, safety and efficacy. The EuroGTPII methodologies were specifically tailored to perform the risk assessment, identify and suggest tests in order to mitigate the potential risk consequences of a novel tissue preparation implementation. Methods: The new allograft and associated preparation processes were assessed using the EuroGTP methodologies and characterized to properly evaluate the novelty (Step 1), identify and quantify the potential risks and risk consequences (Step 2), and define the extent of pre-clinical and clinical assessments required to mitigate the risks identified in the assessment (Step 3). Results: Four risk consequences associated with the preparation process were identified: (i) implant failure related with tissue procurement and the reagents used during the decellularization protocol; (ii) unwanted immunogenicity related with the processing; (iii) disease transmission linked with the processing, reagents used, reduction in the reliability of microbiology testing and the storage conditions; and (iv) toxicity related to the reagents used and handling of the tissue during clinical application. The outcome of the risk assessment was a low level of risk. Nevertheless, it determined the need for a series of risk mitigation strategies proposed to reduce each individual risk and to provide additional evidence of the safety and efficacy of full-thickness acellular dermal matrix grafts. Conclusion: EuroGTPII methodologies allow us to identify the risks and ensure the correct definition of pre-clinical assessments required to address and mitigate the potential risk consequences, before proceeding with clinical use of the new allografts in patients.

Decellularized Graft for Repairing Severe Peripheral Nerve Injuries in Sheep.

BACKGROUND AND OBJECTIVES: Peripheral nerve injuries resulting in a nerve defect require surgical repair. The gold standard of autograft (AG) has several limitations, and therefore, new alternatives must be developed. The main objective of this study was to assess nerve regeneration through a long gap nerve injury (50 mm) in the peroneal nerve of sheep with a decellularized nerve allograft (DCA). METHODS: A 5-cm long nerve gap was made in the peroneal nerve of sheep and repaired using an AG or using a DCA. Functional tests were performed once a month and electrophysiology and echography evaluations at 6.5 and 9 months postsurgery. Nerve grafts were harvested at 9 months for immunohistochemical and morphological analyses. RESULTS: The decellularization protocol completely eliminated the cells while preserving the extracellular matrix of the nerve. No significant differences were observed in functional tests of locomotion and pain response. Reinnervation of the tibialis anterior muscles occurred in all animals, with some delay in the DCA group compared with the AG group. Histology showed a preserved fascicular structure in both AG and DCA; however, the number of axons distal to the nerve graft was higher in AG than in DCA. CONCLUSION: The decellularized graft assayed supported effective axonal regeneration when used to repair a 5-cm long gap in the sheep. As expected, a delay in functional recovery was observed compared with the AG because of the lack of Schwann cells.

Addressing Risks Derived From the Commodification of Substances of Human Origin: A European Proposal Applicable Worldwide.

In view of the public consultation recently launched by the World Health Organization on Regulatory Convergence of Cell and Gene Therapy Products and the Proposal for a Regulation on substances of human origin (SoHO) repealing the European Union Directives on Blood and on Tissues and Cells, an opportunity arises to define an ethical and transparent framework of collaboration between industry and authorities responsible for SoHO-derived products, comprising medicines, medical devices, transfusion, and transplantation. The commodification of SoHO-derived medicinal products and medical devices entails important risks to the sustainability of healthcare systems and threatens the equitable access of patients to innovative therapies. It may also jeopardize the principle of altruistic donation of SoHO that is required for the treatment and survival of thousands of patients every year. This article puts forward several proposals aimed at reconciling the ethical principles of voluntary and unpaid SoHO donation and the noncommercialization of the human body with obtaining a profit that allows business activities, while ensuring high quality, safety, and efficacy standards of tissues and cells for clinical use.

A Comparative Study Using Fluorescent Confocal Microscopy and Flow Cytometry to Evaluate Chondrocyte Viability in Human Osteochondral Allografts.

The preservation conditions of fresh osteochondral allografts for clinical applications are critical due their objective: to transplant mature hyaline cartilage containing viable chondrocytes, maintaining their metabolic activity and also preserving the structural and functional characteristics of the extracellular matrix. The aim of the present study was to compare fluorescence confocal microscopy and flow cytometry techniques to evaluate the viability of the chondrocytes present in the osteochondral tissue, in order to determine their effectiveness and thus ensure reproducibility and robustness of the analysis. To this end, osteochondral allografts from human cadaveric donors were preserved at 4 °C for 3 weeks in a preservation medium supplemented with antibiotic and antifungal agents. Cell viability of chondrocytes was determined by monitoring the cartilage for 3 weeks of preservation by confocal fluorescence microscopy and flow cytometry, obtaining cell viabilities of 83.7 ± 2.6% and 55.8 ± 7.8% for week three, respectively. The confocal fluorescence microscopy approach is more advantageous and accurate, as it correlates better with actual cell viability values for monitoring osteochondral graft preservation, detecting only the cells that died a natural death associated with the preservation method.

Lyophilized amniotic membrane graft for primary pterygium surgery: preliminary results.

The aim of this study was to investigate the tolerability, safety and efficacy of new lyophilized amniotic membrane (LAM) presentation for ocular use. A prospective case-series cohort of four patients with primary nasal pterygium which undergone excision and LAM implantation was evaluated for complications and clinical outcomes. Surgical manipulation of LAM was also assessed. LAM was stiff and easy to manipulate as well as no tearing occurred during surgery or suturing. Ocular comfort was checked and similar among those patients with LAM glued or sutured. After 12 months, there were no issues about tolerability or adverse events. Lower cosmetic outcomes (recurrence) were stated in 3 patients. Our study showed that LAM could be an effective alternative to cryopreserved amniotic membrane for graft after pterygium excision surgery. Its main advantage, storage at room temperature, can make it of immediate availability. Further studies comparing clinical outcomes of pterygium surgery with cryopreserved amniotic membrane versus LAM would confirm the benefits of the last.

"Off-the-Shelf" Nerve Matrix Preservation.

Background: Decellularized human nerves overcome the limitations of the current treatments for large peripheral nerve injuries. However, the use of decellularized nerves requires an "off-the-shelf" availability for useful and actual clinical application. In this study, we addressed the preservation of the native and decellularized human nerve matrix in an integrative approach for tissue scaffold production. Materials and Methods: For native nerve matrix preservation analysis, we used histological examination and immunofluorescence to examine the structure, biomechanical assays to evaluate the tensile strength and Young's modulus, and analyzed the extracellular matrix (ECM) composition using enzyme-linked immunosorbent assay (ELISA) and biochemical assays for laminin, collagen and sulfated glycosaminoglycans (sGAG). After decellularization, nuclear remnants and DNA content were evaluated using 4',6-diamidino-2-phenylindole (DAPI) staining and the picogreen quantification assay, as well as immunofluorescence or ELISA for cell rests (S100 protein and myelin staining) evaluation. Decellularized cryopreserved scaffolds were assayed for biomechanics, ECM composition, and structural maintenance. Cytotoxicity assays were performed to evaluate the biocompatibility of the nerve matrix extracts after cryopreservation. Results: We compared different strategies for native nerve storage and found that preservation up to 7 days at 4°C in Roswell Park Memorial Institute medium maintained biomechanical properties, such as Young's modulus and tensile strength, along with the structure and ECM composition, regarding laminin, collagen, and sGAG. After a successful decellularization process, that eliminated cell remnants, nerve scaffolds were frozen in an "in house" formulated cryoprotectant, using an automatic controlled rate freezer. Nerve structure, ECM composition, and biomechanical properties were maintained before and after the freezing process in comparison with native nerves. The extracts of the nerve scaffolds after thawing were not cytotoxic and the freezing process sustained good viability in 3T3 cells (graphical abstract). Conclusion: Since our approach facilitates transport, storage, and provide a ready-to-use alternative, it could be used in a clinical application for the treatment of long-gap peripheral nerve injuries in regenerative medicine.

Amniotic membrane extract eye drops: a new approach to severe ocular surface pathologies.

A protocol for processing amniotic membrane as an extract to be re-hydrated and administered topically as eye drops (amniotic membrane extract eye drops, AMEED) has been developed. Safety and efficacy of AMEED was assessed in patients with severe ocular surface pathologies. prospective clinical follow-up of ocular surface symptoms before and after regular application of the AMEED for at least 4 weeks on patients with severe ocular surface disorders as chronic dry eye disease, limbal stem cell deficiency, neurotrophic ulcer and permanent and disabling symptomatology that were refractory to conventional treatment. Efficacy and tolerability were assessed based on patient-reported symptoms, objective measurements, and reports of adverse events. Thirty-six eyes from 25 patients were included. Although the visual quality function score, by means of a VQF25 questionnaire, was not statistically different after the treatment (p = 0.4657), there was a clear trend, statistically significant, towards the improvement in ocular symptoms like foreign body sensation, itching and stinging (p < 0.05) and clinical presentation of the pathology. All patients with corneal ulcer showed complete epithelization. Topically applied AMEED proved to be safe, well tolerated and effective in reducing the symptoms and clinical signs of severe ocular disease. Further studies are needed to confirm the best indications for AMEED use.

30†A new step on amniotic membrane extract eye drops (AMEED) development for the treatment of severe ocular surface pathologies.

INTRODUCTION: Our tissue establishment developed a protocol for processing amniotic membranes as extracts to be re-hydrated and administered topically as eye drops, becoming a new approach to treat severe ocular surface pathologies. From 2015 to 2017 the safety and efficacy of the amniotic membrane extract eye drops (AMEED) were assessed in patients with severe ocular surface pathologies through clinical follow-up of ocular surface symptoms before and after regular application of the extract.Between 2018 and 2019 a study of 36 patients (50 eyes) treated with topical AMEED was conducted comparing 2 groups of patients: Dry Eye Disease (DED) and Wound Healing Delay (WHD) showing global similar symptomatic improvement in both groups (DED 88.9% vs WHD 100%; p= 0.486) with the WHD group especially consisting in general relief (78%) and DED group reporting more pain improvement (44%) (p=0.011). Regarding patients with autologous serum as previous treatment, no statistical differences were found in subjective or objective improvement. An overall success was achieved in 94.4% of the cases and no adverse events were found. From January 2020 to November 2021 a growth stage has been observed including more patients while optimizing and scaling the process from donation to clinical use. MATERIALS AND METHODS: We record data of placenta donation and preparation of AMEED vials from 1/1/2020 to 30/11/2021 and its clinical use including the indications for treatment, number of requesting ophthalmologists and number of patients. RESULTS: In the study period a total of 378 placentas were processed to obtain AMEDD (61 in 2020 and 317 in 2021). The number of suitable vials obtained were: 1845 and 6464 respectively and 1946 vials are stored in quarantine pending release for clinical use.A total of 9365 vials were sent for treatment of ocular surface pathologies to 31 hospitals (98% in Catalonia) and 69 requesting ophthalmologists.The total number of patients treated was 204 and the indications for treatment were 82% DED and 18% WHD. CONCLUSION: After the new product development and introduction stages, a significant increase in the use of AMEED in Catalan hospitals was observed in 2020-2021. Follow-up data of these patients should be assessed to demonstrate its efficacy and achieve the maturity stage.

38†Lyophilized amniotic membrane for pterygium surgery: long-term outcomes.

PURPOSE: To investigate the tolerability, security and long-term efficacy of lyophilized amniotic membrane (LAM) as an alternative to cryopreserved amniotic membrane in pterygium surgery. MATERIAL AND METHODS: Prospective case series of patients with primary nasal pterygium who undergone pterygium surgery and LAM implant either with sutures or glue. Postoperative follow-up was until month 24. Clinical and cosmetic outcomes, quality of life (as ocular comfort), and complications were evaluated. RESULTS: LAM was stiff and easy to manipulate as well as no tearing occurred during surgery or suturing. 4 patients (3 males) had pterygium surgery and LAM implant two with sutures and the other two with glue. Ocular comfort was checked and similar among those patients with LAM glued or sutured. After 24 months, there were no issues about tolerability or adverse events. Lower cosmetic outcomes (recurrence) were stated in 3 patients. CONCLUSION: Our study showed that LAM could be an effective alternative to cryopreserved amniotic membrane for graft after pterygium excision surgery. Its main advantage, storage at room temperature, can make it of immediate availability. Further studies comparing clinical outcomes of pterygium surgery with cryopreserved amniotic membrane versus LAM would confirm the benefits of the last.

4†New strategies in the barcelona eye bank to minimize the impact of the COVID-19 pandemic.

Since the start of the pandemic, the tissue donation in Catalonia (Spain) has decreased drastically. At the beginning of the lockdown (from March to May 2020) there was a drop of around 70% in donation of corneas and of approximately 90% in donation of placentas. Despite the fast updating of standard operating procedures, we had big difficulties in different points. For instance, in the availability of the transplant coordinator for the donor detection and evaluation, in obtaining the necessary PPE (personal protective equipment), or in the resources available in the quality control laboratories for screening. This, added to the collapse that hospitals suffered due to the large number of patients hospitalized each day, made donation levels slowly rebound.In order to provide solutions to all patients, we tried to adapt quickly to these emerging changes.In the case of corneas, we found a scenario that we had never had before. Although the cornea transplant plummeted at the beginning of the confinement (decreased by 60% compared to 2019), we run out of corneas -even for emergency situations- at the end of March.This situation led us to develop a new type of therapeutic solution in our Eye Bank. The cryopreserved cornea for tectonic purposes is a tissue that is kept frozen at -196°C and can be preserved for up to 5 years. Therefore, it is a tissue that allows us to respond to possible emergencies in subsequent similar situations.Regarding amniotic membrane for ocular care indications, the strategy was completely different. For this kind of tissue, we carried out an adaptation of our processing with two different purposes. On the one hand, to make sure that we could inactivate the SARS-CoV-2 virus, if it was there. On the other hand, to increase the donation of placentas. For this, changes in the transport medium and in the antibiotic cocktail were performed. In addition, an irradiation step was added to the final product.Little by little, it seems that the donations of corneas and placentas have been recovering. However, it is necessary to think about future contingency strategies in case a stop in donation is repeated.

Cord blood and amniotic membrane extract eye drop preparations display immune-suppressive and regenerative properties.

Diseases and injuries that compromise the ocular surface cause considerable patient distress and have long term consequences for their quality of life. Treatment modalities that can address the delicate balance of tissue regeneration, inflammation and maintenance of corneal transparency are therefore needed. We have recently formulated two novel eye drops from placental tissues: cord blood platelet lysate (CBED) and amniotic membrane extract eye drops (AMED), which can be used to treat severe ocular disorders. Here we characterise these two preparations by measuring: (a) growth factors (GF) and cytokines composition, (b) promotion of human corneal epithelial cell (HCEC) growth and (c) effects on immune cells in a lymphocyte culture assay. Finally, their bioavailability was assayed in an ex vivo porcine corneal model. We show that both preparations contain GF and cytokines that were able to promote the in vitro growth of HCEC and support repair in an in vitro scratch test. When assessed in a lymphocyte culture, both favoured immune suppression reducing the cellular expression of NKG2D and CD107a as well as the production of interferon gamma (IFN-γ) in natural killer, NKT and T cells. Regarding bioavailability, CBED active molecules were found mainly in the pre-corneal fraction with some penetration into the corneal fraction, in an ex vivo model. In summary, both placental-derived allogeneic preparations, CBED and AMED, display regenerative and immunomodulatory capabilities. These results will help define mechanisms of action and the best indications and doses of each product for use in a particular patient and support the development of off-the-shelf therapies for ocular surface pathologies in which wound healing defects and inflammatory events are contributing factors.

Amniotic membrane extract eye drops for ocular surface diseases: use and clinical outcome in real-world practice.

PURPOSE: To study the indications and clinical outcomes, in a real-word setting, of amniotic membrane extract eye drops (AMEED) use for ocular surface disease (OSD). METHODS: A retrospective study of patients treated with topical AMEED between January 2018 and January 2020 was conducted. Patients were classified in two groups according to specific OSD-dry eye disease (DED) and wound healing delay (WHD) groups. Demographics, comorbidities, treatment duration and clinical outcomes were analysed. RESULTS: A total of 50 eyes of 36 patients with or without previous treatments were included. Patients in the DED group presented more systemic comorbidities (83 vs 22%; p < 0.001) and spent more mean time under AMEED treatment (10 vs 7.2 months average) than the WHD group (p = 0.0104). In four patients, long-term treatment (more than 24 months) was reported. Global similar symptomatic improvement was reported for both groups (DED 88.9% vs WHD 100%; p = 0.486), with the WHD group especially consisting in general relief (78%) and the DED group reporting more pain improvement (44%) (p = 0.011). Regarding patients with autologous serum as a previous treatment, no statistical differences were found in subjective or objective improvement. An overall success was achieved in 94.4% of the cases and no adverse events were found. CONCLUSION: AMEED administration is a promising mean to treat OSD such as dry eye, persistent epithelial defect and corneal ulcers. Although AMEED may be effective in the treatment of severe DED and persistent epithelial defect or corneal ulcers, conclusions are limited owing to the absence of controlled clinical trials.

SARS-CoV-2/COVID-19 pandemic: first wave, impact, response and lessons learnt in a fully integrated Regional Blood and Tissue Bank. A narrative report.

BACKGROUND: The COVID-19 pandemic is placing blood and tissue establishments under unprecedented stress, putting its capacity to provide the adequate care needed at risk. Here we reflect on how our integrated organisational model has faced the first impact of the pandemic and describe what challenges, opportunities and lessons have emerged. MATERIALS AND METHODS: The organisational model of the Catalan Blood and Tissue Bank (Banc de Sang i Teixits, BST) is described. The new scenario was managed by following international recommendations and considering the pandemic in a context of volatility, uncertainty, complexity, and ambiguity (VUCA), allowing rapid measures to be taken. These aimed to: ensure donor safety, promote proper responses to patients' needs, ensure the health and well-being of personnel, and prepare for future scenarios. RESULTS: The BST has adapted its activities to the changes in demand. No shortage of any product or service occurred. Donor acceptance, safety and wellbeing were maintained except for tissue donation, which almost completely stopped. To support the health system, several activities have been promoted: large-scale convalescent plasma (CP) production, clinical trials with CP and mesenchymal stromal cells, massive COVID-19 diagnoses, and participation in co-operative research and publications. Haemovigilance is running smoothly and no adverse effects have been detected among donors or patients. DISCUSSION: Several elements have proven to be critical when addressing the pandemic scenario: a) the early creation of a crisis committee in combination with technical recommendations and the recognition of a VUCA scenario; b) identification of the strategies described; c) the integrated donor-to-patient organisational model; d) active Research and Development (R&D); and e) the flexibility of the staff. It is essential to underline the importance of the need for centralised management, effective contingency strategies, and early collaboration with peers.

Extrinsic modulation of integrin α6 and progenitor cell behavior in mesenchymal stem cells.

Mesenchymal stem cells (MSC) are heterogeneous cells of complex nature that show different potentials while different culture conditions can modify their functionalities through interactions with the microenviroment. Here, we found that bone marrow (BM) MSC from different donor sources and passages that expressed higher levels of α6 integrin subunit (ITGA6), showed higher clonogenicity, migration and differentiation potential. ITGA6 showed important roles improving these potentials and regulating proliferation through protein kinase B (AKT) pathway and cell cycle inhibitor proteins p53 and p21. Moreover, ITGA6 downregulation impaired migration. Cell confluence regulated ITGA6, increasing its expression in low density cultures and decreasing in high density cultures. Besides, ITGA6- cells expressed ITGA6 when seeded at low densities. We found higher ITGA6 expression on fibronectin substrates at lower confluency. Fibronectin increased proliferation, clonogenicity, activation of AKT, decreased cell cycle inhibitor proteins and augmented growth factors expression. Spheres-derived MSC showed higher ITGA6 expression and enhanced potentials for migration, clonogenicity and proliferation. In conclusion, though there is an intrinsic regulation of ITGA6 expression, associated to the progenitor potential of BM-MSC, this expression is regulated by culture conditions and is translated in changes in cell behavior and proliferation. This knowledge could be used to enhance the potential of BM-MSC for clinical application.

First-in-human PeriCord cardiac bioimplant: Scalability and GMP manufacturing of an allogeneic engineered tissue graft.

BACKGROUND: Small cardiac tissue engineering constructs show promise for limiting post-infarct sequelae in animal models. This study sought to scale-up a 2-cm2 preclinical construct into a human-size advanced therapy medicinal product (ATMP; PeriCord), and to test it in a first-in-human implantation. METHODS: The PeriCord is a clinical-size (12-16 cm2) decellularised pericardial matrix colonised with human viable Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs). WJ-MSCs expanded following good manufacturing practices (GMP) met safety and quality standards regarding the number of cumulative population doublings, genomic stability, and sterility. Human decellularised pericardial scaffolds were tested for DNA content, matrix stiffness, pore size, and absence of microbiological growth. FINDINGS: PeriCord implantation was surgically performed on a large non-revascularisable scar in the inferior wall of a 63-year-old male patient. Coronary artery bypass grafting was concomitantly performed in the non-infarcted area. At implantation, the 16-cm2 pericardial scaffold contained 12·5 × 106 viable WJ-MSCs (85·4% cell viability; <0·51 endotoxin units (EU)/mL). Intraoperative PeriCord delivery was expeditious, and secured with surgical glue. The post-operative course showed non-adverse reaction to the PeriCord, without requiring host immunosuppression. The three-month clinical follow-up was uneventful, and three-month cardiac magnetic resonance imaging showed ~9% reduction in scar mass in the treated area. INTERPRETATION: This preliminary report describes the development of a scalable clinical-size allogeneic PeriCord cardiac bioimplant, and its first-in-human implantation. FUNDING: La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, "La Caixa" Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund.

Which type of bone releases the most vancomycin? Comparison of spongious bone, cortical powder and cortico-spongious bone.

Bone infections can be challenging to treat and can lead to several surgeries and relapses. When a graft is needed, cavitary bone loss can be grafted with cancellous or cortical bone. Both can be used for grafting. However, the antibiotic releasing capacity of these grafts has not been compared. Which type of bone is best at releasing the most antibiotic has not been well established. The aim of this study was to determine which type of bone is best for antibiotic release when the bone is suffused with antibiotics by the surgeon. The hypothesis is that there would be a difference between the type of bone tested due to different release capacities of cortical and cancellous bone. This was an experimental study. Cortical spongy bone in chips, Spongy bone in chips and demineralized cortical bone powder were compared. For each type of bone, 5 samples were tested. Processed and decontaminated grafts were freeze-dried to be kept at room temperature. The primary endpoint was the amount of vancomycin released by the graft as it affects the concentration of antibiotic around the graft in clinical practice. The procedure for the study consisted of full graft immersion in a vancomycin solution. Then, the liquid was removed with aspiration. In order to measure the quantity of antibiotic released, the bone was put into distilled water in agitation in a heated rocker at 37 °C. After 30 min of soaking, 1 mL of the liquid was removed. The same extraction process was also carried out after 60 min soaking, 2 h, 3 h, 24 h, and 48 h. No differences were found between each type of bone relative to the concentration of vancomycin released at each time of the assessment. There was a significant difference in the weight of the bone with a higher weight for the cortical powder (1.793 g) versus cortical spongy bone and spongy bone (1.154 g and 1.013 g) with a p value < 0.0001. A significant difference was seen in the weight of the bone with vancomycin after the aspiration of the liquid with 3.026 g for cortical powder, 2.140 g and 2.049 g for the cortical spongy bone and the spongy bone with a p value < 0.0001. In daily clinical practice, one can use cancellous bone, cortico-cancellous bone or cortical powder in order to add vancomycin to a bone graft. Our results show the release kinetics of the soaked allografts. With a maximum of 14 mg/mL in the first minutes and a rapid decrease it shows a pattern comparable to antibiotic loaded bone cement. The method used appears favourable for prophylactic use, protecting the graft against contamination at implantation, but is not sufficient for treating chronic bone infection. LEVEL OF EVIDENCE: V.