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Latest in Tissue Engineering Commercialisation

Latest publications for our pre-accelerator programme community - click below to join for free!

The TERMIS-EU pre-accelerator programme (PAP) consists primarily of online webinars delivered by experienced speakers via GoToWebinar.

Webinars are recorded and uploaded to our YouTube channel, and freely available to access at termisbpc.org/pre-accelerator/

Next webinar: "Regulation"

19th December 2016, 2:00-3:40pm GMT

Register for free at: termisbpc.org/pap3/

Speakers:

  • Dr Christopher Bravery, Director, Consulting on Advanced Biologicals Ltd., UK
  • Dr Julian Hitchcock, Counsel, Denoon Legal, London, UK

Topics:

  • Overview of the regulatory pathways available for ATMPs and other TERM products, including medical device classifications
  • Key regulatory requirements for developing ATMPs in the EU
  • Necessary ancillary activities for regulatory approvals
  • Commercial case study

Explore this collection, click a card

Research Paper

The fabrication and characterization of a multi-laminate, angle-ply collagen patch for annulus fibrosus repair.

Abstract: One major limitation of intervertebral disc (IVD) repair is that no ideal biomaterial has been developed that effectively mimics the angle-ply collagen architecture and mechanical properties of the native annulus fibrosus (AF). Furthermore, it would be beneficial to devise a simple, scalable process by which to manufacture a biomimetic biomaterial that could function as a mechanical repair patch to be secured over a large defect in the outer AF that will support AF tissue regeneration. Such a biomaterial would: (1) enable the employment of early-stage interventional strategies to treat IVD degeneration (i.e. nucleus pulposus arthroplasty); (2) prevent IVD re-herniation in patients with large AF defects; and (3) serve as a platform to develop full-thickness AF and whole IVD tissue engineering strategies. Due to the innate collagen fibre alignment and mechanical strength of pericardium, a procedure was developed to assemble multi-laminate angle-ply AF patches derived from decellularized pericardial tissue. Patches were subsequently assessed histologically to confirm angle-ply microarchitecture, and mechanically assessed for biaxial burst strength and tensile properties. Additionally, patch cytocompatibility was evaluated following seeding with bovine AF cells. This study demonstrated the effective removal of porcine cell remnants from the pericardium, and the ability to reliably produce multi-laminate patches with angle-ply architecture using a simple assembly technique. Resultant patches demonstrated their inherent ability to resist biaxial burst pressures reminiscent of intradiscal pressures commonly borne by the AF, and exhibited tensile strength and modulus values reported for native human AF. Furthermore, the biomaterial supported AF cell viability, infiltration and proliferation. Copyright © 2016 John Wiley & Sons, Ltd.

Pub.: 13 Dec '16, Pinned: 15 Dec '16

Research Paper

Basic science of regenerative biology and application to regenerative medicine: Past, present, and future

Abstract: The concept of tissue regeneration is ancient; the earliest known written reference to it is found in Hesiod’s Theogony. Prometheus’ liver regenerated after being consumed. This type of tissue regeneration is known as regenerative hypertrophy. Regenerative biology advanced significantly in the 18th and 19th centuries and it was during this period that the first reference to the term “stem cell” was recorded; however, the term was used significantly differently than the definition it contains today (a clonal entity able to self-renew and displays asymmetric division). Although the history of regenerative medicine, regenerative biology, and tissue regeneration is ancient, significant findings have occurred in the 18th and 19th centuries, and recently, after a period of neglect, many findings of these time frames have resurfaced and changed the way the field experts understand regenerating tissue. This translates itself into regenerative medicine regarding how to think about the technologies available to the clinician practicing regenerative medicine. That is, basic science should guide the clinical use of available methods and tools used. The tools themselves (eg, cellular therapy) are not synonymous with the practice of regenerative medicine. Rather they are tools in the arsenal of the practicing physician. The goal of this article is to provide an overview of the history of regenerative biology and medicine, the progression of the basic science of regenerative biology, and to include discussions that are focused on translating the basic science of regenerative biology into regenerative medicine. This is not a structured and comprehensive review of all the history and aspects of regenerative biology and regenerative medicine, but merely incorporates several key points to provide evidence of the topics discussed in this article.

Pub.: 05 Dec '16, Pinned: 15 Dec '16

Research Paper

Accelerated craniofacial bone regeneration through dense collagen gel scaffolds seeded with dental pulp stem cells.

Abstract: Therapies using mesenchymal stem cell (MSC) seeded scaffolds may be applicable to various fields of regenerative medicine, including craniomaxillofacial surgery. Plastic compression of collagen scaffolds seeded with MSC has been shown to enhance the osteogenic differentiation of MSC as it increases the collagen fibrillary density. The aim of the present study was to evaluate the osteogenic effects of dense collagen gel scaffolds seeded with mesenchymal dental pulp stem cells (DPSC) on bone regeneration in a rat critical-size calvarial defect model. Two symmetrical full-thickness defects were created (5 mm diameter) and filled with either a rat DPSC-containing dense collagen gel scaffold (n = 15), or an acellular scaffold (n = 15). Animals were imaged in vivo by microcomputer tomography (Micro-CT) once a week during 5 weeks, whereas some animals were sacrificed each week for histology and histomorphometry analysis. Bone mineral density and bone micro-architectural parameters were significantly increased when DPSC-seeded scaffolds were used. Histological and histomorphometrical data also revealed significant increases in fibrous connective and mineralized tissue volume when DPSC-seeded scaffolds were used, associated with expression of type I collagen, osteoblast-associated alkaline phosphatase and osteoclastic-related tartrate-resistant acid phosphatase. Results demonstrate the potential of DPSC-loaded-dense collagen gel scaffolds to benefit of bone healing process.

Pub.: 10 Dec '16, Pinned: 15 Dec '16

Research Paper

Exosome-like silica nanoparticles: a novel ultrasound contrast agent for stem cell imaging.

Abstract: Ultrasound is critical in many areas of medicine including obstetrics, oncology, and cardiology with emerging applications in regenerative medicine. However, one critical limitation of ultrasound is the low contrast of target tissue over background. Here, we describe a novel cup-shaped silica nanoparticle that is reminiscent of exosomes and that has significant ultrasound impedance mismatch for labelling stem cells for regenerative medicine imaging. These exosome-like silica nanoparticles (ELS) were created through emulsion templating and the silica precursors bis(triethoxysilyl)ethane (BTSE) and bis(3-trimethoxysilyl-propyl)amine (TSPA). We found that 40% TSPA resulted in the exosome like-morphology and a positive charge suitable for labelling mesenchymal stem cells. We then compared this novel structure to other silica structures used in ultrasound including Stober silica nanoparticles (SSN), MCM-41 mesoporous silica nanoparticles (MSN), and mesocellular foam silica nanoparticles (MCF) and found that the ELS offered enhanced stem cell signal due to its positive charge to facilitate cell uptake as well as inherently increased echogenicity. The in vivo detection limits were <500 cells with no detectable toxicity at the concentrations used for labelling. This novel structure may eventually find utility in applications beyond imaging requiring an exosome-like shape including drug delivery.

Pub.: 08 Dec '16, Pinned: 15 Dec '16

Research Paper

Effect of small molecules on cell reprogramming

Abstract: The essential idea of regenerative medicine is to fix or replace tissues or organs with alive and patient-specific implants. Pluripotent stem cells are able to indefinitely self-renew and differentiate into all cell types of the body which makes them a potent substantial player in regenerative medicine. The easily accessible source of induced pluripotent stem cells may allow obtaining and cultivating tissues in vitro. Reprogramming refers to regression of mature cells to its initial pluripotent state. One of the approaches affecting pluripotency is the usage of low molecular mass compounds that can modulate enzymes and receptors leading to the formation of pluripotent stem cells (iPSCs). It would be great to assess the general character of such compounds and reveal their new derivatives or modifications to increase the cell reprogramming efficiency. Many improvements in the methods of pluripotency induction have been made by various groups in order to limit the immunogenicity and tumorigenesis, increase the efficiency and accelerate the kinetics. Understanding the epigenetic changes during the cellular reprogramming process will extend the comprehension of stem cell biology and lead to potential therapeutic approaches. There are compounds which have been already proven to be or for now only putative inducers of the pluripotent state that may substitute for the classic reprogramming factors (Oct3/4, Sox2, Klf4, c-Myc) in order to improve the time and efficiency of pluripotency induction. The effect of small molecules on gene expression is dosage-dependent and their application concentration needs to be strictly determined. In this review we analysed the role of small molecules in modulations leading to pluripotency induction, thereby contributing to our understanding of stem cell biology and uncovering the major mechanisms involved in that process.

Pub.: 22 Nov '16, Pinned: 15 Dec '16

Research Paper

Core-shell silk hydrogels with spatially tuned conformations as drug-delivery system.

Abstract: Hydrogels of spatially controlled physicochemical properties are appealing platforms for tissue engineering and drug delivery. In this study, core-shell silk fibroin (SF) hydrogels of spatially controlled conformation were developed. The core-shell structure in the hydrogels was formed by means of soaking the preformed (enzymatically crosslinked) random coil SF hydrogels in methanol. When increasing the methanol treatment time from 1 to 10 min, the thickness of the shell layer can be tuned from about 200 to about 850 μm as measured in wet status. After lyophilization of the rehydrated core-shell hydrogels, the shell layer displayed compact morphology and the core layer presented porous structure, when observed by scanning electron microscopy. The conformation of the hydrogels was evaluated by Fourier transform infrared spectroscopy in wet status. The results revealed that the shell layer possessed dominant β-sheet conformation and the core layer maintained mainly random coil conformation. Enzymatic degradation data showed that the shell layers presented superior stability to the core layer. The mechanical analysis displayed that the compressive modulus of the core-shell hydrogels ranged from about 25 kPa to about 1.1 MPa by increasing the immersion time in methanol. When incorporated with albumin, the core-shell SF hydrogels demonstrated slower and more controllable release profiles compared with the non-treated hydrogel. These core-shell SF hydrogels of highly tuned properties are useful systems as drug-delivery system and may be applied as cartilage substitute. Copyright © 2016 John Wiley & Sons, Ltd.

Pub.: 07 Dec '16, Pinned: 13 Dec '16

Research Paper

Bioengineered Renal Cell Therapy Device for Clinical Translation.

Abstract: The Bioartificial Renal Epithelial Cell System (BRECS), is a cell-based device to treat acute kidney injury through renal cell therapy from an extracorporeal circuit. To enable widespread implementation of cell therapy, the BRECS was designed to be cryopreserved as a complete device, cryostored, cryoshipped to an end-use site, thawed as a complete device, and employed in a therapeutic extracorporeal hemofiltration circuit. This strategy overcomes storage and distribution issues that have been previous barriers to cell therapy. Previous BRECS housings produced by Computer Numerical Control (CNC) machining, a slow process taking hours to produce one bioreactor, was also prohibitively expensive (>$600/CNC-BRECS); major obstacles to mass production. The goal of this study was to produce a BRECS to be mass produced by injection molding (IM-BRECS), decreasing cost (<$20/unit) and improving manufacturing speed (hundreds of units/hr), while maintaining the same cell therapy function as the previous CNC-BRECS, first evaluated through prototypes produced by stereolithography (SLA-BRECS). The finalized IM-BRECS design had a significantly lower fill volume (10 mL), mass (49 g) and footprint (8.5 cm×8.5 cm×1.5 cm), and was demonstrated to outperform the previous BRECS designs with respect to heat transfer, significantly improving control of cooling during cryopreservation and reducing thaw times during warming. During in vitro culture, IM-BRECS performed similarly to previous CNC-BRECS with respect to cell metabolic activity (lactate production, oxygen consumption and glutathione metabolism) and amount of cells supported.

Pub.: 07 Dec '16, Pinned: 13 Dec '16

Research Paper

Neovascularization Induced by the Hyaluronic Acid-Based Spongy-Like Hydrogels Degradation Products

Abstract: Neovascularization has been a major challenge in many tissue regeneration strategies. Hyaluronic acid (HA) of 3–25 disaccharides is known to be angiogenic due to its interaction with endothelial cell receptors. This effect has been explored with HA-based structures but a transitory response is observed due to HA burst biodegradation. Herein we developed gellan gum (GG)-HA spongy-like hydrogels from semi-interpenetrating network hydrogels with different HA amounts. Enzymatic degradation was more evident in the GG-HA with high HA amount due to their lower mechanical stability, also resulting from the degradation itself, which facilitated the access of the enzyme to the HA in the bulk. GG-HA spongy-like hydrogels hyaluronidase-mediated degradation lead to the release of HA oligosaccharides of different amounts and sizes in a HA content-dependent manner which promoted in vitro proliferation of human umbilical cord vein endothelial cells (HUVECs) but not their migration. Although no effect was observed in human dermal microvascular endothelial cells (hDMECs) in vitro, the implantation of GG-HA spongy-like hydrogels in an ischemic hind limb mice model promoted neovascularization in a material-dependent manner, consistent with the in vitro degradation profile. Overall, GG-HA spongy-like hydrogels with a sustained release of HA oligomers are valuable options to improve tissue vascularization, a critical issue in several applications in the tissue engineering and regenerative medicine field.

Pub.: 18 Nov '16, Pinned: 05 Dec '16

Research Paper

Biologic and Tissue Engineering Strategies for Tendon Repair

Abstract: Abstract This review summarizes recent developments in biologic treatments—including growth factors, platelet-rich plasma (PRP), stem cells, and cell-seeded scaffolds—for tendon repair. Growth and differentiation faction-5 (GDF-5), insulin-related growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) all improved extracellular matrix (ECM) production and tensile strength of treated tendons; however, no clinical trials were done on GDF-5. Platelet-derived growth factor-BB (PDGF-BB) improved proliferation and ECM production, but did not consistently improve mechanical properties. The literature was mixed on the efficacy of PRP for the treatment of chronic and acute tendinopathies. However, PRP did cause any complications, and its benefits may be enhanced once an ideal, standardized composition is developed. Therefore, PRP may be a valid treatment, especially once nonsurgical management options have failed. Mesenchymal stem cells (MSCs) significantly and substantially improved the quality of tendon repairs and demonstrated the ability to regenerate an enthesis. Adipose-derived stem cells (ADSCs) have similar effects and are easier to harvest. The periosteum may also regenerate the tendon–bone attachment. Tenocytes, meanwhile, may be ideal for midsubstance tendon repairs. Cell-seeded scaffolds—especially ECM-derived scaffolds—were demonstrated to improve ECM production, enhancing the healing abilities of tenocytes or stem cells while providing early mechanical support to healing tendons. Each of these treatments demonstrated enhanced healing compared to common surgical techniques; moreover, patient outcomes may be enhanced by combining these treatments. Lay Summary Tendon injuries are very prevalent and can be debilitating. Tendon heals poorly, and the scar tissue that forms is weak and susceptible to reinjury. A major focus of orthopedic research is regenerative medicine, encouraging the formation of healthy tendon rather than mechanically inferior scar tissue. This review summarizes the recent scientific literature on biologic treatments for tendon repair, such as growth factors, platelet-rich plasma, and stem cells. The purpose of which is to show which treatments are promising candidates for clinical use and research, helping to guide physicians and to lay out a path for future research. Abstract This review summarizes recent developments in biologic treatments—including growth factors, platelet-rich plasma (PRP), stem cells, and cell-seeded scaffolds—for tendon repair. Growth and differentiation faction-5 (GDF-5), insulin-related growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) all improved extracellular matrix (ECM) production and tensile strength of treated tendons; however, no clinical trials were done on GDF-5. Platelet-derived growth factor-BB (PDGF-BB) improved proliferation and ECM production, but did not consistently improve mechanical properties. The literature was mixed on the efficacy of PRP for the treatment of chronic and acute tendinopathies. However, PRP did cause any complications, and its benefits may be enhanced once an ideal, standardized composition is developed. Therefore, PRP may be a valid treatment, especially once nonsurgical management options have failed. Mesenchymal stem cells (MSCs) significantly and substantially improved the quality of tendon repairs and demonstrated the ability to regenerate an enthesis. Adipose-derived stem cells (ADSCs) have similar effects and are easier to harvest. The periosteum may also regenerate the tendon–bone attachment. Tenocytes, meanwhile, may be ideal for midsubstance tendon repairs. Cell-seeded scaffolds—especially ECM-derived scaffolds—were demonstrated to improve ECM production, enhancing the healing abilities of tenocytes or stem cells while providing early mechanical support to healing tendons. Each of these treatments demonstrated enhanced healing compared to common surgical techniques; moreover, patient outcomes may be enhanced by combining these treatments. AbstractThis review summarizes recent developments in biologic treatments—including growth factors, platelet-rich plasma (PRP), stem cells, and cell-seeded scaffolds—for tendon repair. Growth and differentiation faction-5 (GDF-5), insulin-related growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) all improved extracellular matrix (ECM) production and tensile strength of treated tendons; however, no clinical trials were done on GDF-5. Platelet-derived growth factor-BB (PDGF-BB) improved proliferation and ECM production, but did not consistently improve mechanical properties. The literature was mixed on the efficacy of PRP for the treatment of chronic and acute tendinopathies. However, PRP did cause any complications, and its benefits may be enhanced once an ideal, standardized composition is developed. Therefore, PRP may be a valid treatment, especially once nonsurgical management options have failed. Mesenchymal stem cells (MSCs) significantly and substantially improved the quality of tendon repairs and demonstrated the ability to regenerate an enthesis. Adipose-derived stem cells (ADSCs) have similar effects and are easier to harvest. The periosteum may also regenerate the tendon–bone attachment. Tenocytes, meanwhile, may be ideal for midsubstance tendon repairs. Cell-seeded scaffolds—especially ECM-derived scaffolds—were demonstrated to improve ECM production, enhancing the healing abilities of tenocytes or stem cells while providing early mechanical support to healing tendons.Each of these treatments demonstrated enhanced healing compared to common surgical techniques; moreover, patient outcomes may be enhanced by combining these treatments. Lay Summary Tendon injuries are very prevalent and can be debilitating. Tendon heals poorly, and the scar tissue that forms is weak and susceptible to reinjury. A major focus of orthopedic research is regenerative medicine, encouraging the formation of healthy tendon rather than mechanically inferior scar tissue. This review summarizes the recent scientific literature on biologic treatments for tendon repair, such as growth factors, platelet-rich plasma, and stem cells. The purpose of which is to show which treatments are promising candidates for clinical use and research, helping to guide physicians and to lay out a path for future research. Lay SummaryTendon injuries are very prevalent and can be debilitating. Tendon heals poorly, and the scar tissue that forms is weak and susceptible to reinjury. A major focus of orthopedic research is regenerative medicine, encouraging the formation of healthy tendon rather than mechanically inferior scar tissue. This review summarizes the recent scientific literature on biologic treatments for tendon repair, such as growth factors, platelet-rich plasma, and stem cells. The purpose of which is to show which treatments are promising candidates for clinical use and research, helping to guide physicians and to lay out a path for future research.

Pub.: 21 Nov '16, Pinned: 30 Nov '16

Research Paper

The Influence of Timing and Frequency of Adipose-derived Mesenchymal Stem Cell Therapy on Immunomodulation Outcomes after Vascularized Composite Allotransplantation.

Abstract: Cellular therapies for immunomodulation in vascularized composite allotransplantation (VCA) have gained importance due to their potential minimization of immunosuppression. Adipose-derived mesenchymal stem cells (AD-MSCs) especially have shown encouraging potential. We investigated the influence of timing and frequency of AD-MSC-treatment on immunologic and graft survival as well as graft vasculopathy (GV) outcomes after VCA.Lewis (LEW) rats received full-mismatched Brown Norway (BN) rat hindlimb transplants. Recipient animals were assigned to groups receiving donor-derived AD-MSCs (10 cells/animal) either on postoperative day (POD) 1, POD 4, or repeatedly on POD 4, 8, and 15, and compared to untreated controls.While AD-MSC administration on POD 1 or POD 4,8,15 resulted in 50% long-term graft acceptance, recipients treated on POD 4 and controls rejected prior to POD 50. All treated animals revealed peripheral blood chimerism (4 weeks), most pronounced following repetitive cell administration (12.92% vs. 5.03% [POD 1] vs. 6.31% [POD 4]; p<0.05; all p<0.01 vs. Control 1.45%). Chimerism was associated with the generation of regulatory T cells (CD4CD25FoxP3).In vitro MLRs revealed modulation of the recipient immune response after AD-MSC treatment. Graft arteries at end point revealed significant differences of arterial intimal thickness between rejecting and AD-MSC-treated animals (p<0.01).Taken together, our results point to the potential for repetitive AD-MSC administration in improving outcomes after VCA. Future studies are warranted into optimization of the AD-MSC therapy dosing and frequency, combination with other cell therapies (such as HSC or BM-MSC or dendritic cells) as selection of appropriate conditioning or maintenance regimens.

Pub.: 29 Nov '16, Pinned: 30 Nov '16