MatriDerm

MatriDerm®

A newer generation of artificial biological dermal substitute that is gaining wider acceptance for use in the clinics recently is MatriDerm®. Made up of bovine collagen and an elastin hydrolysate, this product is touted for use in a single-stage procedure. MatriDerm® was shown to be able to accommodate split thickness skin autograft safely in one step with no compromise in take on burn injuries and it seemed to be feasible for use in critically ill patientsIt was suggested that unlike Integra^TM which has antigenic properties due to the presence of chondroitin-6-sulfate, the combination of collagen and elastin in MatriDerm® can promote vascularization quicker through the support of in-growth cells and vessels while improving stability and elasticity of regenerating tissue. Furthermore, higher rate of degradation and difference in neodermal thickness of MatriDerm® compared to Integra^TM  might give the former an extra edge; even though there is still relatively weak scientific evidence on their comparison in the current literature

Integra® Dermal Regeneration Template Single Layer "Thin"

Integra^TM   

                        

Being the most widely accepted artificial biological dermal substitute , the use of Integra^TM which is made up of bovine collagen and chondroitin 6-sulfate, has been reported to give good aesthetic and functional outcomes when compared to using split thickness skin autograft alone . However, it is known that infection still remains the most commonly reported complication of Integra^TM . Meticulous wound bed preparation before the use of this template (or similar type of artificial biological materials) has been reported to be critical to ensure good take. Otherwise with the collection of hematomas and seromas beneath the material, the product is susceptible to infection resulting in a costly loss of an expensive tissue-engineered product and manpower time, while increasing the length of hospital stay for the patient.

Integra^® Dermal Regeneration Template Single Layer "Thin"

Integra^® Dermal Regeneration Template Single Layer "Thin" is the latest extension of Integra's collagen range of dermal repair products. Since the introduction of IDRT in 1996, the brand portfolio has expanded to include single layer, bilayer and flowable versions. This latest addition reinforces the company's proven advanced collagen technology for more than 20 years in a variety of indications, including life-threatening burns, scar revisions and diabetic foot ulcers.

"The European clinical community has been looking forward to the market release of Integra Single Layer Thin, the thinnest dermal substitute available," said Stéphane Corp, vice president of Tissue Technologies in Europe.  "We will now be able to provide plastic and reconstructive surgeons a thinner matrix for dermal repair they can use in a single-stage procedure, while maintaining the same aesthetic and functional benefits of a two-stage procedure, which will ultimately reduce overall hospital stays for patients."

Birth of skin tissue engineering

Skin tissue engineering rat racing:  A coincidence?

The year 1975 seems to be a special year for skin tissue engineering, even before the term “tissue engineering” was officially adopted more than a decade later by the Washington National Science Foundation bioengineering panel meeting in 1987 [5] and later its definition elucidated further by Langer and Vacanti [6] in 1993. The beginnings of skin tissue engineering can be attributed to the pioneering work of two groups in the United States forty years ago. First, Rheinwald and Green reported the successful serial cultivation of human epidermal keratinocytes in vitro [7] in 1975 and later made possible the expansion of these cells into multiple epithelia suitable for grafting [8] from a small skin biopsy. In today’s term, the work is termed “tissue engineering of the skin epidermis”. Concurrently, Yannas, Burke and colleagues reported their maiden work on the in vitro and in vivo characterization of collagen degradation rate [9] in 1975 which we believe pave the way for the design of artificial biological dermal substitute [10], resulting in the “tissue engineering of the skin dermis”.

Another coincidence?

Interestingly, six years later in 1981, both groups independently reported the clinical use of their respective tissue-engineered substitutes for the treatment of severe and extensive burns, albeit in different approaches. O’Connor et al. reported the world’s first grafting of extensive burns with sheets of cultured epithelium (expanded from autologous epidermal cells) on two adult patients with success at the Peter Bent Brigham Hospital [11, 12]. These autologous cultured sheets (Fig. 2) termed cultured epidermal autografts (CEA) were also subsequently demonstrated to provide permanent coverage of extensive full thickness burns in another two paediatric patients [13].

Meanwhile, Burke et al. (a few months after O’Connor et al.’s report) reported the successful use of a physiologically acceptable artificial dermis in the treatment of extensive burn injuries with full thickness component on ten patients [14]. This was followed by a randomized clinical trial for major burns led by Heimbach et al. [15] on the use of this artificial dermis, now known as Integra^TM Dermal Regeneration Template. This successful multi-centre study involving eleven centres and many other studies [16, 17] might have inevitably given this dermal substitute a “gold standard” status for full thickness burns treatment [18].

While ground breaking, the work of the above two groups are still far from reaching the ultimate goal of replacing skin autografts for permanent coverage of deep dermal or full thickness wounds in extensive burns.

Tissue engineering of replacement skin

The holy grail of creating a fully functional tissue-engineered composite skin

As much as it is claimed that tissue-engineered skin is now a reality to treat severe and extensive burns, the fact remains that current skin substitutes available are still fraught with limitations for clinical use. This is clearly evident amongst burns or wound-care physicians that there is currently no single tissue-engineered substitute which can fully replicate the spilt-thickness skin autografts for permanent coverage of deep dermal or full thickness wounds in a one-step procedure. Indeed, clinical practice for severe burn treatments have since evolved to incorporate some of these tissue-engineered skin substitutes.

3D Printing market

Modeling Human Kidney Biology

Nephrotoxicity is of increasing concern in the drug development pipeline and the kidney proximal tubule is the primary site of renal toxicity. Conventional preclinical renal assays, such as in vitro cell culture and animal models, often fail to accurately model the complexity of organ toxicity seen in drug responses due to limited functionality or species-specific variation.
ExVive™ Human Kidney Tissue is a fully human 3D bioprinted tissue comprised of an apical layer of polarized primary renal proximal tubule epithelial cells (RPTECs) supported by a collagen IV-rich tubulointerstitial interface of primary renal fibroblasts and endothelial cells.
Tissues are printed under stringent quality controlled conditions and are designed to model native biology and architecture in a highly reproducible manner for optimal preservation of cellular function and transporter activity. Epithelial cells form tight junctions and maintain stable gamma glutamyl-transferase activity and native renal transporter expression for multiple weeks in culture.
The cellular and architectural structure of ExVive™ Human Kidney Tissue provides an ideal means to study the many phenotypes of nephrotoxicity including tubular transport of xenobiotics, proteins, and ions.

• Composition and architecture enables the biochemical and histological assessment of human renal toxicity.
• Tissue-like complexity supports the detection of injury, compensation, and recovery.
• Physiological expression of transporters models native transport activity.

Transporter-Mediated Toxicity

Cisplatin is a widely used chemotherapeutic that is well characterized as a nephrotoxicant with multiple modes of action. On its path towards excretion, cisplatin is taken up by RPTECs via transporters such as OCT2. Upon accumulation of cisplatin in the epithelial cells, reactive oxygen species and toxic glutathione conjugates are formed resulting in cell damage and subsequent renal toxicity. Cimetidine, an OCT2 inhibitor, can block the accumulation of cisplatin and the ensuing tissue damage.
Cisplatin-mediated nephrotoxicity and its prevention by cimetidine was shown in ExVive™ Human Kidney Tissue.

• Tissues are treated for 7 days with increasing doses of cisplatin.
• Dose-dependent decrease in overall tissue viability (Resazurin) and epithelial-specific viability (GGT) is observed.
• Biomarkers for renal toxicity, Clusterin and NGAL, are detected in response to insult.
• Inhibition of OCT2 by cimetidine effectively blocks cisplatin-induced toxicity.

NovoView™ Preclinical Safety Testing Services

ExVive™ 3D Bioprinted Kidney Tissues are available through our NovoView™ Preclinical Safety Testing Services that are designed specifically to meet your study requirements. We work closely with you to design an optimal combination of biochemical and histological readouts to assess the physiologically-relevant effects of your compound on human tissues.
At Organovo, we apply state of the art quality control and assurance processes to ensure that our customers can rely on the quality and reproducibility of the data we generate. Our tissue team has years of experience in every step of the bioprinting process, from bioprinting itself to subsequent maintenance, monitoring, and analyses of the ExVive™ Human Kidney Tissues.
Our dedicated team of scientific experts provide comprehensive consultation to determine which parameters best suit your needs.

Clinically-Relevant Answers in Three Simple Steps

 Study Design
Projects are initiated by in-depth consultation with our toxicology experts to define study design details, including time frame, dosing regimen, and readouts.
 Tissue Testing
Customer-provided test articles are evaluated on ExVive™ 3D Bioprinted Tissue generated by our tissue experts.
 Data Evaluation
A comprehensive study report is provided, and reviewed together with Organovo scientists.

Inside L’Oreal’s Plan to 3-D Print Human Skin

L'Oreal makes cosmetics and hair color. It also makes skin. Human skin, created in a lab, so it can test its products without using people or animals. Now it's talking about printing the stuff, using 3-D bioprinters that will spit out dollops of skin into nickel-sized petri dishes.

The idea is to produce skin more quickly and easily using what is essentially an assembly line developed with Organovo, a San Diego bioprinting company. Such a technique would allow the French cosmetics company to do more accurate testing, but it also has medical applications—particularly in burn care.

 Treating severe burns typically involves grafting a healthy patch of skin taken from elsewhere on the body. But large burns present a problem. That has researchers at Wake Forest experimenting with a treatment method that involves applying a small number of healthy skin cells onto the injury and letting them grow organically over the wound. 3-D-bioprinted skin potentially could be produced faster, provided Organovo can successfully replicate the cell structure of human epidermis.

 L’Oreal already has a massive lab in Lyon, France, to produce its patented skin, called Episkin, from incubated skin cells donated by surgery patients. The cells grow in a collagen culture before being exposed to air and UV light to mimic the effects of aging. Organovo pioneered the process of bioprinting human tissues, most notably creating a 3-D-printed liver system. Both parties benefit from the partnership: L’Oreal gets Organovo’s speed and expertise, and Organovo gets funding and access to L’Oreal’s comprehensive knowledge of skin, acquired through many years and over $1 billion in research and development.

 At the moment, L'Oreal uses its epidermis samples to predict as closely as possible how human skin will react to the ingredients in its products. If L'Oreal can more quickly iterate on the molecular composition of its skin samples, it can produce more accurate results, conceivably across different skin phenotypes. That means products like sunscreen and age-defying serums—which inevitably will yield varying results across varying skin types—can be tweaked for greater efficacy.L'Oreal also has a history of selling Episkin to other cosmetic and pharmacology companies. The company won’t disclose the going rate, but in 2011 told Bloomberg it sold half-centimeter-wide samples for €55 each (about $78 each at the time). That said, Guive Balooch, who runs L’Oreal’s in-house tech incubator, says the bioprinting will be done primarily for research purposes.

The French cosmetics giant has partnered bioprinting startup Organovo to figure out how to 3D print living, breathing derma that can be used to test products for toxicity and efficacy.
“We’re the first beauty company Organovo has worked with,” says Guive Balooch, global vice president of L’Oreal’s tech incubator.
The firm is already growing more than 100,000 skin samples annually, but under the current method, skin samples are grown from tissues donated by plastic surgery patients in France are then cut into thin slices and broken down into cells.
With San Diego-based Organovo’s help, L’Oreal aims to speed up and automate skin production within the next five years.
Research for the project will take place in Organovo’s labs and L’Oreal’s new California research center. L’Oreal will provide skin expertise and all the initial funding, while Organovo, which is already working with such companies as Merck to print liver and kidney tissues, will provide the technology.
Organovo has already made headlines with claims that it can 3D-print a human liver but this is its first tie-up with the cosmetics industry.
Its statement explaining the advantage of printing skin, offered little detail: “Our partnership will not only bring about new advanced in vitro methods for evaluating product safety and performance, but the potential for where this new field of technology and research can take us is boundless.”
It also gave no timeframe for when printed samples would be available, saying it was in “early stage research”.
However, printed skin has more value in a medical scenario, potentially creating stores of spare skins for burn victims.