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Posts Tagged ‘Tissue engineering’


Skin Regeneration Therapy One of First Tissue Engineering Products Evaluated by FDA

Reporter: Irina Robu, PhD

Under the provisions of 21st Century Cures Act the U.S. Food and Drug Administration approved StrataGraft regenerative skin tissue as the first product designated as a Regenerative Medicine Advanced Therapy (RMAT) produced by Mallinckrodt Pharmaceuticals. StrataGraft is shaped using unmodified NIKS cells grown under standard operating procedures since the continuous NIKS skin cell line has been thoroughly characterized. StrataGraft products are virus-free, non-tumorigenic, and offer batch-to-batch genetic consistency.

Passed in 2016, the 21st Century act allows FDA to grant accelerated review approval to products which meet an RMAT designation. The RMAT designation includes debates of whether priority review and/or accelerated approval would be suitable based on intermediate endpoints that would be reasonably likely to predict long-term clinical benefit.

The designation includes products

  • defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products;
  • intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
  • preliminary clinical evidence indicates the drug has the potential to address unmet medical needs for such disease or condition.

According to Steven Romano, M.D., Chief Scientific Officer and Executive Vice President, Mallinckrodt “We are very pleased the FDA has determined StrataGraft meets the criteria for RMAT designation, as this offers the possibility of priority review and/or accelerated approval. The company tissue-based therapy is under evaluation in a Phase 3 trial to assess its efficacy and safety in the advancement of autologous skin regeneration of complex skin defects due to thermal burns that contain intact dermal elements.

SOURCE

https://www.rdmag.com/news/2017/07/skin-regeneration-therapy-one-first-be-evaluated-fda

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Fibrin-coated Electrospun Polylactide Nanofibers Potential Applications in Skin Tissue Engineering

Reported by: Irina Robu, PhD

 

Fibrin plays an essential role during wound healing and skin regeneration and is often applied for the treatment of skin injuries. Fibrin is formed after thrombin cleavage of fibrinopeptide A from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. Double-stranded fibrils form through end-to-middle domain (D:E) associations, and concomitant lateral fibril associations and branching create a clot network. In addition, its primary role is to provide scaffolding for the intravascular thrombus.

Dr. Lucie Bacakova and her colleagues from Department of Biomaterials and Tissue engineering at Czech Academy of Sciences prepared electrospun nanofibrious membranes made from poly(L-lactide) modified with a thin fibrin nanocoating. The cell-free fibrin nanocating remained stable in cell culture medium for 14 days and did not change its morphology. The rate of fibrin degradation is correlated to the degree of cell proliferation on membrane populated with human dermal fibroblasts. It was shown that the cell spreading, mitochondrial activity and cell population density were higher on membranes coated with fibrin than on nonmodified membranes. The cell performance was improved by adding ascorbic acid in the cell culture medium. At the same time, fibrin stimulated the expression and synthesis of collagen I in human dermal fibroblasts. The expression of beta-integrins was improved by fibrin. And it is shown that the combination of nanofibrous membranes with a fibrin nanocoating and ascorbic acids is beneficial to tissue engineering.

Source

https://www.dovepress.com/articles.php?article_id=25743#

 

 

 

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New Scaffold-Free 3D Bioprinting Method Available to Researchers

Reporter: Irina Robu, PhD

 

UPDATED ON 2/6/2016

Kenzan

SOURCE

Bio 3D Printer Regenova with Kenzan method

http://https://www.3dprintingbusiness.directory/news/kenzan-method-3d-bioprinting-cyfuses-regenova-system/

SOURCE

Cyfuse and Cyberdyne Are Pushing the Boundaries of 3D Printed Human Engineering With Regenova

by TE Halterman | Mar 3, 2015 | 3D Printers3D PrintingHealth 3D Printing |

http://3dprint.com/48312/cyfuse-and-cyberdyne-3d-printed-human-engineering/

 

Scafold-free

SOURCE

PUBLIC RELEASE: 3-FEB-2016

New scaffold-free 3-D bioprinting method available for first time in North America

Cell Applications primary cells and Regenova 3D Bio Printer from Cyfuse Biomedical combine to print robust 3-D tissue without introduction of extraneous scaffolding material

 

VIEW VIDEO

Regenova, Bio 3D Printer by Cyfuse

 

Cyfuse Biomedical K.K. and Cell Applications.Inc. publicized on February 3, 2016 that advanced tissue engineering services using 3D bioprinting approach will be available in North America. The services involved using Cyfuse Biomedica’s Regenova 3D Bio Printer, a state of the art robotic system that produces 3D tissues from cell and Cell Applications has created a pay by service bio-printing model that produces scaffold-free tissue available immediately to scientists in the U.S. and Canada for research use.

According to James Yu, Founder and CEO of Cell Applications having the Regenova 3D Bio Printer at our San Diego headquarters offers researchers an end-to-end, customized solution for creating scaffold-free, 3D-engineered tissues that diminish costs by reducing the lengthy processes typical in pharmaceutical drug discovery. In addition , Koji Kuchiishi, CEO of Cyfuse Biomedical having the Regenova 3D Bio Printer, combined with Cell Applications’ comprehensive, high-quality primary cell bank, offers researchers streamlined access to a nearly limitless selection of three dimensional tissues including those mimicking blood vessels, human neural tissue and liver constructs.

Unlike the other bioprinters on the market the bio-printer made by Regenova does not depend on scaffolding made of biomaterials such as collage or hydrogel to construct 3D tissue, the instrument assembles three dimensional microscopic tissue by forming spheroids, one at the time and lancing them on a fine needle array. The spheroids are guided by pre-programmed software which can be design and constructed into rods, spheres, tubes, sheets and other tissue configurations. In order for the engineered tissue to mature a bioreactor chamber is used. As the cells mature, they self-organize promoting strong, reliable tissue that can be further optimized by design of bio printer’s needle array that allows for optimum circulation of culture medium.

Source
http://www.cyfusebio.com/en/

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Cells from Cow Knee Joints Used to Grow New Cartilage Tissue

Reported by: Irina Robu, PhD

Researchers at Umea University in Sweden used cartillage cell from cow knee joints in an effort to help lead to a new treatment cure for osteoarthritis using stem cell-based tissue engineering. Osteoarthritis can mean the loss of the entire cartilage tissue in the joint. While the condition causes pain and immobility for the individual, it also loads society with extra medical costs.

In their experiments, the researchers at Umeå University developed new methods to produce cartilage-like “neotissues” in a laboratory enviroment. In the engineering process, the cells, the signaling molecules and the scaffold, i.e. artificial support material, are combined to regenerate tissue at the damaged site in the joint.

Using primary bovine chondrocytes, i.e. cartilage cells from cows, the researchers improved methods to grow cartilage tissue in a laboratory environment, producing tissue similar to tissue normally present in the human joints. In the future, these results may help the development of neocartilage production for actual cartilage repair.

Source

http://www.mdtmag.com/news/2016/01/cells-cow-knee-joints-used-grow-new-cartilage-tissue

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Three-dimensional printed microfibers used to reinforce hydrogels

Reporter: Irina Robu, PhD

The field of tissue engineering has continued to evolve with the intention to restore, replace and regenerate loss and damaged tissues. Engineered tissues have been able to help millions of people which why their development and design is important. The tree components that are needed for this are cells, scaffold and bioactive factors. 

The scaffold is responsible for providing the structure and support needed to provide tissue development but they differ in composition, design, material properties, structure properties etc. In the spite of everything,  the concept of a scaffold is to mimic the function of the native extracellular matrix by creating similar architectural, biological and mechanical features.

One classic material that is used for tissue engineering are hydrogels, which are designed to provide a hydrated 3D environment of the cells which act as cell carriers. But, hydrogels are unable to provide the needed mechanical properties needed to form extracellular matrix.

Taking the account the limitation, scientists from Medical Center at Utrecht University created a 3D dimensional microfiber network through melt electrospinning to reinforce hydrogel architecture, in order to provide mechanical and biological stable environment for engineered constructs. They took into account that they hydrogel mechanical properties should match those of the target tissue to promote enhanced performance. 

Researchers in the past have tried to mimic  the architecture of native tissues including reinforced nanofibers, woven scaffolds, non-woven scaffolds and microfibers. The typical manufacturing technique used is electrospinning which is advantageous because it creates a more accurate structural mimic of the native tissue extracellular matrix. 

In the study published by researchers at University of Utrecht Medical Center, use melt electrospinning. This electrospinning assembles the fibers layer by layer, supplying regulated control over assembly architecture. The researchers aimed to create a support for gelatin methacrylamide hydrogels with high porosity fiber scaffolds made of poly(ε-caprolactone) (PCL). The composite was created by infusing and crosslinking methacrylamide hydrogels within the PCL scaffolds. To stimulate the level of hydrogel reinforcement, a mathematical model was developed using the scaffold parameters. 

The study showed that the reinforced hydrogel stiffness was identical to that of articular cartilage as it increased up to 54-fold compared to hydrogels or microfiber scaffolds alone. The microfiber network can be used by various types of hydrogels which indicates that  they can offer mechanically and biologically favorable environments for various types of engineered tissues.

This current development in the field of tissue engineering will allow for the creation and use of resistant and effectual hydrogels to treat tissue loss or damage. The organized fibrous PCL scaffolds within the hydrogel allow for a healthy and diversified cell culture environment, because the hydrogel degrades over a few months which allows for new tissue to integrate into the scaffold. The PCL scaffold will in turn disintegrate within years, acting as a reinforcing network that will develop functional tissue. This reinforced hydrogel represents a step towards creating biomechanical functional tissue constructs and hopefully, more research will someday lead to the creation of the ideal, modify according to individual specifications engineered tissue replacement.

Source

http://www.nature.com/ncomms/2015/150428/ncomms7933/full/ncomms7933.html#access

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Curator: Aviva Lev-Ari, PhD, RN

The history of gold nanoparticles in the use of advanced Medicine is about 15 years old. Dr. Barliya wrote on Diagnosing lung cancer in exhaled breath using gold  in 12/2012.nanoparticles

Alchemia commented on an MIT NEWS article on “New cardiac patch uses gold nanowires to enhance electrical signaling between cells” 9/26, 2011

I would respectfully point out that the use of almost nano sized gold particles carrying a positive electrical charge have been developed and used as ultrafine colloidal gold for over ten years and used as a treatment helping to maintain the heart’s natural rhythm, as well as for helping calm the effects of brain related limb tremors.

This ultrafine colloidal gold has also been used successfully to help calm and control the entire neural system and relieve stress related neural pain over the same past ten year period using Ultrafine Colloidal Gold by Alchemedica Intl.

It is in the light of your brilliant nano technology breakthrough, that we feel our own pioneering efforts developing and pushing the boundery in the field of ultrafine colloidal gold, silver, copper and zinc vindicated.

I salute your unorthodox approach and its successful conclusion”

http://web.mit.edu/newsoffice/2011/gold-nanowire-heart-0926.html

As an Introduction to the Genetics of Conduction Disease, we selected the following article which represents the MOST comprehensive review of the Human Cardiac Conduction System presented to date:

I. The Cardiac Conduction System

  1. David S. Park, MD, PhD;
  2. Glenn I. Fishman, MD

Circulation.2011; 123: 904-915 doi: 10.1161/​CIRCULATIONAHA.110.942284

II.  On the Genetics of the Human Conduction System

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

III. A Promise for the MI Patient: A new cardiac patch uses Gold Nanowires to enhance Electrical Signaling between heart cells

Key term: 

Colloidal gold is a suspension (or colloid) of sub-micrometre-sized particles of gold in a fluid – usually water. The liquid is usually either an intense red colour (for particles less than 100 nm), or blue/purple (for larger particles).[1][2][3] Due to theunique optical, electronic, and molecular-recognition properties of gold nanoparticles, they are the subject of substantial research, with applications in a wide variety of areas, including electron microscopyelectronicsnanotechnology,[4][5] andmaterials science.

Properties and applications of colloidal gold nanoparticles strongly depend upon their size and shape.[6] For example, rodlike particles have both transverse and longitudinal absorption peak, and anisotropy of the shape affects their self-assembly.[7]

SOURCE and References for the Key term

http://en.wikipedia.org/wiki/Colloidal_gold

A heart of gold

New cardiac patch uses gold nanowires to enhance electrical signaling between cells, a promising step toward better treatment for heart-attack patients.
Emily Finn, MIT News Office 7/25/2013
March 20, 2013
A heart of gold

A scanning electron microscope (SEM) image of nanowire-alginate composite scaffolds. Star-shaped clusters of nanowires can be seen in these images.
IMAGE COURTESY OF THE DISEASE BIOPHYSICS GROUP, HARVARD UNIVERSITY
September 26, 2011
A team of researchers at MIT and Children’s Hospital Boston has built cardiac patches studded with tiny gold wires that could be used to create pieces of tissue whose cells all beat in time, mimicking the dynamics of natural heart muscle. The development could someday help people who have suffered heart attacks.The study, reported this week in Nature Nanotechnology, promises to improve on existing cardiac patches, which have difficulty achieving the level of conductivity necessary to ensure a smooth, continuous “beat” throughout a large piece of tissue.“The heart is an electrically quite sophisticated piece of machinery,” says Daniel Kohane, a professor in the Harvard-MIT Division of Health Sciences and Technology (HST) and senior author of the paper. “It is important that the cells beat together, or the tissue won’t function properly.”

The unique new approach uses gold nanowires scattered among cardiac cells as they’re grown in vitro, a technique that “markedly enhances the performance of the cardiac patch,” Kohane says. The researchers believe the technology may eventually result in implantable patches to replace tissue that’s been damaged in a heart attack.

Co-first authors of the study are MIT postdoc Brian Timko and former MIT postdoc Tal Dvir, now at Tel Aviv University in Israel; other authors are their colleagues from HST, Children’s Hospital Boston and MIT’s Department of Chemical Engineering, including Robert Langer, the David H. Koch Institute Professor.

Ka-thump, ka-thump

To build new tissue, biological engineers typically use miniature scaffolds resembling porous sponges to organize cells into functional shapes as they grow. Traditionally, however, these scaffolds have been made from materials with poor electrical conductivity — and for cardiac cells, which rely on electrical signals to coordinate their contraction, that’s a big problem.

“In the case of cardiac myocytes in particular, you need a good junction between the cells to get signal conduction,” Timko says. But the scaffold acts as an insulator, blocking signals from traveling much beyond a cell’s immediate neighbors, and making it nearly impossible to get all the cells in the tissue to beat together as a unit.

VIEW VIDEO
Video courtesy of the Disease Biophysics Group, Harvard University
Video courtesy of Youtube.com
To solve the problem, Timko and Dvir took advantage of their complementary backgrounds — Timko’s in semiconducting nanowires, Dvir’s in cardiac-tissue engineering — to design a brand-new scaffold material that would allow electrical signals to pass through.“We started brainstorming, and it occurred to me that it’s actually fairly easy to grow gold nanoconductors, which of course are very conductive,” Timko says. “You can grow them to be a couple microns long, which is more than enough to pass through the walls of the scaffold.”

From micrometers to millimeters

The team took as their base material alginate, an organic gum-like substance that is often used for tissue scaffolds. They mixed the alginate with a solution containing gold nanowires to create a composite scaffold with billions of the tiny metal structures running through it.

Then, they seeded cardiac cells onto the gold-alginate composite, testing the conductivity of tissue grown on the composite compared to tissue grown on pure alginate. Because signals are conducted by calcium ions in and among the cells, the researchers could check how far signals travel by observing the amount of calcium present in different areas of the tissue.

“Basically, calcium is how cardiac cells talk to each other, so we labeled the cells with a calcium indicator and put the scaffold under the microscope,” Timko says. There, they observed a dramatic improvement among cells grown on the composite scaffold: The range of signals conduction improved by about three orders of magnitude.

“In healthy, native heart tissue, you’re talking about conduction over centimeters,” Timko says. Previously, tissue grown on pure alginate showed conduction over only a few hundred micrometers, or thousandths of a millimeter. But the combination of alginate and gold nanowires achieved signal conduction over a scale of “many millimeters,” Timko says.

“It’s really night and day. The performance that the scaffolds have with these nanomaterials is just much, much better,” Kohane says.

“It’s very beautiful work,” says Charles Lieber, a professor of chemistry at Harvard University. “I think the results are quite unambiguous, and very exciting — both in showing fundamentally that they’ve improved the conductivity of these scaffolds, and then how that clearly makes a difference in enhancing the collective firing of the cardiac tissue.”

The researchers plan to pursue studies in vivo to determine how the composite-grown tissue functions when implanted into live hearts. Aside from implications for heart-attack patients, Kohane adds that the successful experiment “opens up a bunch of doors” for engineering other types of tissues; Lieber agrees.

“I think other people can take advantage of this idea for other systems: In other muscle cells, other vascular constructs, perhaps even in neural systems, this is a simple way to have a big impact on the collective communication of cells,” Lieber says. “A lot of people are going to be jumping on this.”

 

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Author: Tilda Barliya PhD

Annual treatment costs for musculoskeletal diseases in the US are roughly 7.7% (~ $849 billion) of total gross domestic product. Such disorders are the main cause of physical disability in US (I). The challenges of drug delivery for bone regeneration and reconstruction has been previously reported here by Dr. Aviral Vatsa (I-IV), herein, we will discussed the different needs for bone regeneration and the potential use if nanotechnology.

Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis (1,2).

Regenerative medicine offers a way to improve  ‘local’ strategies in terms of tissue engineering and gene therapy, or even ‘systemic’ enhancement of bone repair. To make regenerative medicine successful, three elements are required: stem cells, scaffolds, and growth factors (3).

Bones

Bone is a tough supporting tissue and functions in both movement and the maintenance of postural stability by working cooperatively with muscles as well as play a role in calcium metabolism. Despite its hard structure it exist in a dynamic turnover known as bone remodeling. There are two types of bone structures that naturally remodel during the a year:

  • cortical bone (~3%/year)
  • cancellous bone (~30%/year)
148261.fig.001

Jimi J et al. The schematic outlines of the bone remodeling cycle and the balance of bone resorption and bone formation

At the remodeling sites, osteoblasts produce new bone, while osteoclasts resorb existing bone. Each cell type seems to be regulated by a variety of hormones and by local factors. If the balance between bone formation and resorption is lost by uncontrolled production of these regulators, the bone structure will be damaged, and the subject would be susceptible to osteoporosis and osteopetrosis (2).

Current Clinical approaches:

Standard approaches widely used in clinical practice to stimulate or augment bone regeneration include distraction osteogenesis and bone transport.

As well as the use of a number of different bone-grafting methods, such as (1):

  • Autologous bone grafts – considered as the ‘gold standard‘ bone-grafting material, as it combines all properties required in a bone-graft material: osteoinduction (bone morphogenetic proteins (BMPs) and other growth factors), osteogenesis (osteoprogenitor cells) and osteoconduction (scaffold)
  • Allografts – obtained from human cadavers or living donors, which bypasses the problems associated with harvesting and quantity of graft material. Allogeneic bone is available in many preparations, including demineralised bone matrix (DBM), morcellised and cancellous chips, corticocancellous and cortical grafts, and osteochondral and whole-bone segments, depending on the recipient site requirements.
  • Bone-graft substitutes or growth factors – developed as alternatives to autologous or allogeneic bone grafts. They consist of scaffolds made of synthetic or natural biomaterials that promote the migration, proliferation and differentiation of bone cells for bone regeneration. Commonly performed surgical procedure to augment bone regeneration in a variety of orthopaedic and maxillofacial procedures.

The Masquelet technique is a two-step procedure for bone regeneration and reconstruction of long-bone defects. It is based on the concept of a “biological” membrane, which is induced after application of a cement spacer at the first stage and acts as a ‘chamber’ for the insertion of non-vascularised autograft at the second stage (2, 4).

There are  non-invasive methods of biophysical stimulation, such as low-intensity pulsed ultrasound (LIPUS) and pulsed electromagnetic fields (PEMF) (1).

Limitations of Current approaches: Most of the current strategies for bone regeneration exhibit relatively satisfactory results. However, there are associated drawbacks and limitations to their use and availability, and even controversial reports about their efficacy and cost-effectiveness.

New Approaches:

New methods for studying this process, such as quantitative three-dimensional microcomputed tomography analyses, finite element modelling, and nanotechnology have been developed to further evaluate the mechanical properties of bone regenerate at the microscopic level. Here are some examples of the latest developments as reviewed by Dimitriou R at el (1).

BMPs and growth factors – They induce the mitogenesis of mesenchymal stem cells (MSCs) and other osteoprogenitors, and their differentiation towards osteoblasts. BMP-2 and BMP-7 have been licensed for clinical use since 2002 and 2001 respectively (5). These two molecules have been used in a variety of clinical conditions including non-union, open fractures, joint fusions, aseptic bone necrosis and critical bone defects. Platelet-derived growth factor (PDFG), transforming growth factor-β (TGF-b), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) have been also implicated in bone regeneration, with different functions in terms of cell proliferation, chemotaxis and angiogenesis. One current approach to enhance bone regeneration and soft-tissue healing by is local application of growth factors is the use of platelet-rich plasma alongside the autograph. BMPs are also being used in bone-tissue engineering.

MSCs – The current approach of delivering osteogenic cells directly to the regeneration site includes use of bone-marrow aspirate from the iliac crest, which also contains growth factors. It is a minimally invasive procedure to enhance bone repair, and produces satisfactory results (1). Overall, however, there are significant ongoing issues with quality control with respect to delivering the requisite number of MSCs/osteoprogenitors to effect adequate repair responses. Issues of quantity and alternative sources of MSCs are being extensively investigated. Novel approaches in terms of cell harvesting, in vitro expansion and subsequent implantation are promising.

Scaffolds and Bone substitutes – synthetic bone substitutes and biomaterials are already widely used in clinical practice for osteoconduction. DBM (Demineralized bone matrix)  and collagen are biomaterials, used mainly as bone-graft extenders, as they provide minimal structural support. A large number of synthetic bone substitutes are currently available, such as HA, β-TCP and calcium-phosphate cements, and glass ceramics. These are being used as adjuncts or alternatives to autologous bone grafts. Especially for regeneration of large bone defects, where the requirements for grafting material are substantial, these synthetics can be used in combination with autologous bone graft, growth factors or cells (6). Improved biodegradable and bioactive three-dimensional porous scaffolds are being investigated, as well as novel approaches using nanotechnology, such as magnetic biohybrid porous scaffolds acting as a crosslinking agent for collagen for bone regeneration guided by an external magnetic field or injectable scaffolds for easier application.

Tissue Engineering – The tissue-engineering approach is a promising strategy added in the field of bone regenerative medicine, which aims to generate new, cell-driven, functional tissues, rather than just to implant non-living scaffolds. In essence, bone-tissue engineering combines progenitor cells, such as MSCs (native or expanded) or mature cells (for osteogenesis) seeded in biocompatible scaffolds and ideally in three-dimensional tissue-like structures (for osteoconduction and vascular ingrowth), with appropriate growth factors (for osteoinduction), in order to generate and maintain bone (7). Bone-tissue engineering is in its early stages, and there are many issues of efficacy, safety and cost to be addressed before general clinical application can be achieved.

Gene Therapy – This involves the transfer of genetic material into the genome of the target cell, allowing expression of bioactive factors from the cells themselves for a prolonged time. Gene transfer can be performed using a viral (transfection) or a non-viral (transduction) vector, and by either an in vivo or ex vivo gene-transfer strategy. There are issues of cost, efficacy and biological safety that need to be answered.

Nanotechnology and Bone Regeneration

Nanotechnology has been greatly utilized for bone tissue engineering strategies. It has been employed to overcome some of the current limitations associated with bone regeneration methods including insufficient mechanical strength of scaffold materials, ineffective cell growth and osteogenic differentiation at the defect site, as well as unstable and insufficient production of growth factors to stimulate bone cell growth (8,9).

To mimic the natural bone nanocomposite architecture, novel biomaterials and nanofabrication techniques are currently being employed and many different nanostructures have already been designed and tested. Electrospinning has been extensively applied to create bone nanofiber scaffolds and biomaterials typically used for this purpose, including synthetic organic polymers such as PCL, PLGA, PLLA, Chitosan, and silk fibroin.

Among the materials used for bone-reconstruction, PLLA is a biocompatible polymer with the advantage of being highly. biodegradable. For this reason, PLLA have received the approval of the Food and Drug Administration (FDA) to be use in bone reconstructive surgery (10).

PLLA nanofibers are often functionalized to improve their biological performance with peptides such as RGD (Arg-Gly-Asp); with osteogenic molecules such as hydroxyapatite; or with proteins such as collagen and the growth factor bone morphogenic protein 2 (BMP-2). It was found that direct incorporation of BMP-2 into PLLA nanofibers enhances the osteoinductivity of the scaffolds.

Current orthopedic implants fail in an appropriate osteo-integration limiting implant lifespan. Titanium, as a biocompatible material, has been used to enhance implant incorporation in bone for dental, craniofacial, and orthopedic applications. Studies have demonstrated that nanoporous titanium dioxide (TiO2) surface modification alters nanoscale topography improving soft tissue attachment on titanium implants surface (11). For example, the uses of nanoporous TiO2 surface-modified implants, in a human dental clinical study, showed that TiO2 thin film increased adherence in early healing of the human oral mucosa and reduced marginal bone resorption (11).

Another example are rosette nanotubes. Bioactive helical rosette nanotubes are self-assembled nanomaterials, formed in water from synthetic DNA base analogs that mimic the helical nanostructure of collagen in bone. This technology has been used to create a biomimetic nanocomposite combined with nanocrystalline hydroxyapatite, and biocompatible hydrogels which increased osteoblast adhesion.

Carbon nanotubes (CNTs) are other suitable scaffold materials that have proved to support osteoblast proliferation. CNTs possess exceptional mechanical, thermal, and electrical properties, facilitating their use as reinforcements or, in combination with other biomaterials, to improve and to support bone growth.

Nanotechnology and clinical trials

Clinical therapies implying the use of nanotechnology in bone regeneration are still in the beginning stages.

BDSint –  Recently, the bone healing ability of a nanocomposite (DBSint®), approved for clinical use, constituted by biomimetic nanostructured Mg-hydroxyapatite and human demineralized bone matrix has been investigated.  The clinical-radiographic and histomorphometry study in subjects undergoing high tibial osteotomy, demonstrated that these nanocomposites are safe and effective. Yet the long term outcome is still to be defined (8, 12).

BioOsss and BioGides –  Schwarz et al. undertook a four-year study of patients treated of moderate intrabony peri-implantitis defects using either a nanocrystalline hydroxyapatite or a natural bone mineral (BioOsss spongiosa granules) in combination with a collagen membrane (BioGides) and found bone reconstruction (8, 13).

Here are some of the ongoing clinical trials for use of nanotechnology in bone regeneration (Perán M et al (8)):

NCT00729716 – Comparison of BioCart™II With Microfracture for Treatment of Cartilage Defects of the Femoral Condyle BioCart™II scaffold Cartilage ————Phase 2.

NCT01183637  – Evaluation of “Kensey Nash Corp” an Acellular Osteochondral Graft for Cartilage Lesions Pilot Trial (EAGLE Pilot) bioresorbable scaffold Bone/ Cartilage————-Phase 2

NCT01218945 –  Development of Bone Grafts Using Adipose-Derived Stem Cells and Different Scaffolds Bone scaffold Bone——– recruiting participants

NCT01435434 – Mononucleotide Autologous Stem Cells and Demineralized Bone Matrix in the Treatment of Non-Union/Delayed Fractures Ignite®ICS injectable scaffold Bone——————Not yet recruiting

Summary:

The advantages of nanomaterials as therapeutic and diagnostic tools are vast, due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification.  The potential of these bio-devices has shown promising results in vitro, and some of them have also been successfully tested in vivo with animal models. Nevertheless, the gap between laboratory and medical application of these nanotechnological advances is still wide (8).

Although some successful devises have already being tested in clinical trials and the data produced by these studies is highly encouraging, the safety of nanomedicine is not yet fully defined and more clinical studies still need to be conducted to translate nanotechnological devices to the clinic.

Reference:

1. Dimitriou R, Jones E, McGonagle D and Giannoudis P.V. Bone regeneration: current concepts and future directions. BMC Medicine 2011, 9:66. http://www.biomedcentral.com/1741-7015/9/66

2. Jimi E.,  Hirata S., Osawa K.,  Terashita M., Kitamura C.,  and Fukushima H. The Current and Future Therapies of Bone Regeneration to Repair Bone Defects. International Journal of Dentistry Volume 2012 (2012), Article ID 148261. doi:10.1155/2012/148261. http://www.hindawi.com/journals/ijd/2012/148261/

3. G. C. Gurtner, M. J. Callaghan, and M. T. Longaker, “Progress and potential for regenerative medicine,” Annual Review of Medicine, vol. 58, pp. 299–312, 2007. http://www.ncbi.nlm.nih.gov/pubmed/17076602

4. Masquelet AC, Begue T: The concept of induced membrane for reconstruction of long bone defects. Orthop Clin North Am 2010, 41(1):27-37. http://www.ncbi.nlm.nih.gov/pubmed/19931050

5. Food and Drug Administration: Medical devices. [http:/ / www.fda.gov/ MedicalDevices/ ProductsandMedicalProcedures/ DeviceApprovalsandClearances/ Recently-ApprovedDevices/ default.htm

6. Giannoudis PV, Dinopoulos H, Tsiridis E: Bone substitutes: an updateInjury 2005, 36(Suppl 3):S20-27. http://www.ncbi.nlm.nih.gov/pubmed/16188545

7. Jones E, English A, Churchman SM, Kouroupis D, Boxall SA, Kinsey S, Giannoudis PG, Emery P, McGonagle D: Large-scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum 2010, 62(7):1944-1954.  http://onlinelibrary.wiley.com/doi/10.1002/art.27451/abstract;jsessionid=4573A69E4561194C83A97EC302CD20CB.d04t02

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Other articles from our Open Access Journal

I. By: Aviral Vatsa PhD MBBS. Targeted delivery of therapeutics to bone and connective tissues: current status and challenges- Part I. https://pharmaceuticalintelligence.com/2012/09/23/targeted-delivery-of-therapeutics-to-bone-and-connective-tissues-current-status-and-challenges-part-i/

II. By: Aviral Vatsa PhD MBBS. Targeted delivery of therapeutics to bone and connective tissues: current status and challenges- Part II. https://pharmaceuticalintelligence.com/2012/09/30/targeted-delivery-of-therapeutics-to-bone-and-connective-tissues-current-status-and-challenges-part-ii/

III. By: Aviral Vatsa PhD MBBS. Osteocytes: A Special Issue in Bone.  https://pharmaceuticalintelligence.com/2013/02/06/osteocytes-a-special-issue-in-bone/

IV. By: Aviral Vatsa PhD MBBS. Bone remodelling in a nutshell. https://pharmaceuticalintelligence.com/2012/06/22/bone-remodelling-in-a-nutshell/

V. By: Ritu Saxena PhD. Dual protection of bone by Sema3a. https://pharmaceuticalintelligence.com/2012/05/10/dual-protection-of-bone-by-sema3a-2/

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