Tag Archives: #scaffolds

How 3D-printed Scaffolds Promotes Tissue Regeneration? (Medicine)

Research published today has demonstrated the viability of 3D-printed tissue scaffolds that harmlessly degrade while promoting tissue regeneration following implantation.

The scaffolds showed highly promising tissue-healing performance, including the ability to support cell migration, the ‘ingrowth’ of tissues, and revascularisation (blood vessel growth).

Professor Andrew Dove, from the University of Birmingham’s School of Chemistry, led the research group and is the lead author on the paper published in Nature Communications, which characterises the physical properties of the scaffolds, and explains how their ‘shape memory’ is key to promoting tissue regeneration.

Professor Dove commented: “The scaffolds have evenly distributed and interconnected pores that allow diffusion of nutrients from surrounding tissues. The shape memory means this structure is retained when the scaffold is implanted into tissues, and this supports the infiltration of cells into the scaffold while encouraging tissue regeneration and revascularisation.”

The scaffolds were created using 3D printing resin ‘inks’ developed during a major programme of biomaterials research led by Professor Andrew Dove at the University of Birmingham and Warwick University. The resins are being commercialised under the tradename 4Degra™ by 4D Biomaterials, a spinout from University of Birmingham Enterprise and Warwick Innovations that was launched in May 2020.

The scaffolds showed several major advantages over current approaches used to fill soft tissue voids that remain after trauma or surgery, including sufficient elasticity to conform to irregular spaces, the ability to undergo compression of up to 85% before returning to their original geometry, compatibility with tissues, and non-toxic biodegradation.

The paper describes several compositions for the 4Degra™ resins that enable materials of a wide range of strengths to be manufactured. All of the compositions include a photoinitiator and a photoinhibitor to ensure the resins rapidly turn into gel on exposure to light in the visible spectrum to enable their 3D printing into a range of scaffold geometries.

The researchers showed that the materials were non toxic to cells and they also performed mechanical testing to ensure the scaffolds could regain their shape, geometry and pore size after compression, and performed tests that showed the scaffolds can fill an irregular shaped void in alginate gel which was used as a mimic of soft tissue.

Laboratory studies demonstrated that the scaffold degrades by surface erosion into non-acidic products, which means the scaffold structure allows for slow, continuous tissue infiltration.

The findings were confirmed in a mouse model that simulates implantation into adipose (fat) tissue. These studies showed infiltration of adipocytes and fibroblasts and vascularisation at two months, and a tissue arrangement and macrophage presence that was indicative of normal tissue restoration rather than damaged, scarred tissue or an inflammatory response.

At four months, the researchers found small, mature blood vessels in the surrounding tissue. The scaffolds also demonstrated excellent biocompatibility. The collagen capsule formed around implants was less than 200 µm thick, which is well below the 500 µm threshold used for biocompatibility in other studies, and there was no calcification or necrosis.

Also at four months, 80% of the scaffold was still present, demonstrating the slow degradation predicted by the laboratory studies, and indicating the scaffolds would provide support for more than a year, allowing sufficient time for mature tissue ingrowth. The controls, which used poly(L-lactic acid) (PLLA) as a comparator, did not show a significant reduction over the four month period.

Professor Dove comments: “3D printed materials have received a lot of attention in the tissue engineering world. However void-filling materials to provide mechanical support, biocompatibility, and surface erosion characteristics that ensure consistent tissue support during the healing process, and this means a fourth dimension (time) needs to be considered in material design.

“We have demonstrated that it’s possible to produce highly porous scaffolds with shape memory, and our processes and materials will enable production of self-fitting scaffolds that take on soft tissue void geometry in a minimally invasive surgery without deforming or applying pressure to the surrounding tissues. Over time, the scaffold erodes with minimal swelling, allowing slow continuous tissue infiltration without mechanical degradation.”

4D Biomaterials has made fast progress in scaling up production of the 4Degra™ resin-inks at its laboratory in MediCity, Nottingham (UK) and is now offering technical grade material for commercial supply to 3D printing companies and medical device manufacturers.

CEO Phil Smith said “We are looking to collaborate with innovative companies in Europe and North America to develop a new generation of 3D-printed medical devices that translate the unique advantages of the 4Degra™ resin-ink platform into improved treatment outcomes for patients”. With the first customer shipments dispatched and a funding round about to close, Phil added “We will be making further announcements shortly.” 

Featured image: Bioresorbable tissue scaffolds © University of Birmingham

This science news has been confirmed by us from University of Birmingham

Provided by University of Birmingham

Bio-inspired Scaffolds Help Promote Muscle Growth (Medicine)

Rice University bioengineers adapt extracellular matrix for electrospinning

Rice University bioengineers are fabricating and testing tunable electrospun scaffolds completely derived from decellularized skeletal muscle to promote the regeneration of injured skeletal muscle.

Their paper in Science Advances shows how natural extracellular matrix can be made to mimic native skeletal muscle and direct the alignment, growth and differentiation of myotubes, one of the building blocks of skeletal muscle. The bioactive scaffolds are made in the lab via electrospinning, a high-throughput process that can produce single micron-scale fibers.

The research could ease the burden of performing an estimated 4.5 million reconstructive surgeries per year to repair injuries suffered by civilians and military personnel.

Current methods of electrospinning decellularized muscle require a copolymer to aid in scaffold fabrication. The Rice process does not.

“The major innovation is the ability to prepare scaffolds that are 100% extracellular matrix,” said bioengineer and principal investigator Antonios Mikos of Rice’s Brown School of Engineering. “That’s very important because the matrix includes all the signaling motifs that are important for the formation of the particular tissue.”

The scaffolds leverage bioactive cues from decellularized muscle with the tunable material properties afforded through electrospinning to create a material rich with biochemical signals and highly specific topography. The material is designed to degrade as it is replaced by new muscle within the body.

Experiments revealed that cells proliferate best when the scaffolds are not saturated with a crosslinking agent, allowing them access to the biochemical cues within the scaffold matrix.

Aligned fibers produced via electrospinning can be used to form a tunable scaffold for growing new muscle, according to Rice University bioengineers. These fibers were fabricated with decellularized skeletal muscle extracellular matrix on a mandrel spinning at 3,000 rotations per minute. Courtesy of the Mikos Research Group

Electrospinning allowed the researchers to modulate crosslink density. They found that intermediate crosslinking led to better retention of fiber alignment during cell culture.

Most decellularized matrix for muscle regeneration comes from such thin membranes as skin or small intestine tissue. “But for muscle, because it’s thick and more complex, you have to cut it smaller than clinically relevant sizes and the original material properties are lost,” said Rice graduate student and lead author Mollie Smoak. “It doesn’t resemble the original material by the time you’re done.

“In our case, electrospinning was the key to make this material very tunable and have it resemble what it once was,” she said.

“It can generate fibers that are highly aligned, very similar to the architecture that one finds in skeletal muscle, and with all the biochemical cues needed to facilitate the creation of viable muscle tissue,” Mikos said.

Mikos said using natural materials rather than synthetic is important for another reason. “The presence of a synthetic material, and especially the degradation products, may have an adverse effect on the quality of tissue that is eventually formed,” he said.

“For eventual clinical application, we may use a skeletal muscle or matrix from an appropriate source because we’re able to very efficiently remove the DNA that may elicit an immune response,” Mikos said. “We believe that may make it suitable to translate the technology for humans.”

Rice University graduate students Katie Hogan, left, and Mollie Smoak prepare to fabricate a scaffold with an electrospinner. The scaffolds derived from decellularized skeletal muscle are designed to promote regeneration of injured skeletal muscle. Photo by Jeff Fitlow

Smoak said the electrospinning process can produce muscle scaffolds in any size, limited only by the machinery.

“We’re fortunate to collaborate with a number of surgeons, and they see promise in this material being used for craniofacial muscle applications in addition to sports- or trauma-induced injuries to large muscles,” she said. “These would include the animation muscles in your face that are very fine and have very precise architectures and allow for things like facial expressions and chewing.”

Co-authors of the paper are Rice graduate student Katie Hogan and Jane Grande-Allen, the Isabel C. Cameron Professor of Bioengineering. Mikos is the Louis Calder Professor of Bioengineering and Chemical and Biomolecular Engineering.

The National Institutes of Health, the National Science Foundation and the Ford Foundation supported the research.

Read the abstract at https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abg4123.

Featured image: Aligned myotubes formed on electrospun extracellular matrix scaffolds produced at Rice University. The staining with fluorescent tags shows cells’ expression of myogenic marker desmin (green), actin (red) and nuclei (blue) after seven days of growth. Courtesy of the Mikos Research Group

Provided by Rice University

Injectable Porous Scaffolds Promote Better, Quicker Healing After Spinal Cord Injuries (Medicine)

Hydrogel scaffolds with regularly spaced pores encourage spinal cords cells to grow, improve regeneration of nerve cells.

Spinal cord injuries can be life-changing and alter many important neurological functions. Unfortunately, clinicians have relatively few tools to help patients regain lost functions.

In APL Bioengineering, by AIP Publishing, researchers from UCLA have developed materials that can interface with an injured spinal cord and provide a scaffolding to facilitate healing. To do this, scaffolding materials need to mimic the natural spinal cord tissue, so they can be readily populated by native cells in the spinal cord, essentially filling in gaps left by injury.

“In this study, we demonstrate that incorporating a regular network of pores throughout these materials, where pores are sized similarly to normal cells, increases infiltration of cells from spinal cord tissue into the material implant and improves regeneration of nerves throughout the injured area,” said author Stephanie Seidlits.

The researchers show how the pores improve efficiency of gene therapies administered locally to the injured tissues, which can further promote tissue regeneration.

Since many spinal cord injuries result from a contusion, the biomaterial implants need to be injected in or near the injured area without causing damage to any surrounding spared tissue. A major technical challenge has been fabricating scaffold materials with cell-scale pore sizes that are also injectable.

In the researchers’ method, they injected beads of material through a small needle into the spinal cord, where the beads stick together to form a scaffold, where cells can crawl in the pore spaces between the beads. The researchers found inclusion of these larger cell-scale pores within biomaterial scaffolds improved cell infiltration, gene delivery, and tissue repair after spinal cord injury, compared to more conventional materials with nanoscale pores.

The researchers made the highly porous scaffolds using two different methods. One was simpler but created a more irregularly sized pore network. The second was more complicated but created a highly regular pore structure.

Even though both materials had the same average pore size and chemical composition, more regenerating nerves were found to infiltrate scaffolds with regularly shaped pores.

“These results inform how to maximize interfacing with the nervous system,” said Seidlits. “This has potential applications not only for developing new therapies for brain and spinal cord repair but also for brain-machine interfaces, prosthetics, and treatment of neurodegenerative diseases.”

The article “Injectable, macroporous scaffolds for delivery of therapeutic genes to the injured spinal cord” is authored by Arshia Ehsanipour, Mayilone Sathialingam, Laila M. Rad, Joseph de Rutte, Rebecca D. Bierman, Jesse Liang, Weikun Xiao, Dino Di Carlo, and Stephanie K. Seidlits. The article will appear in APL Bioengineering on Mar. 9, 2021 (DOI: 10.1063/5.0035291). After that date, it can be accessed at https://aip.scitation.org/doi/10.1063/5.0035291.

Featured image: Images show myelinated axons in biomaterial scaffolds eight weeks after injection into the injured cord of a mouse. Scaffolds were fabricated from hyaluronic acid (HA) with a regular network of cell-scale macropores and loaded with gene therapy vectors encoding for brain-derived neurotrophic factor (BDNF), to promote axonal survival and regeneration. These were compared to control scaffolds, which were lacking the BDNF vector. Images show dense infiltration of cells (shown in blue, cell nuclei), axons (shown in red in A, NF200 protein) and myelinating glial cells (shown in green, myelin basic protein) in the BDNF-laden scaffolds. Scale bars = 200 μm. © Seidlits et al.

Provided by American Institute of Physics

Tissue Filler, Scaffold Technologies Provide New Options For Patients with Breast Cancer, Other Diseases (Medicine)

New technology from Purdue University innovators may help improve tissue restoration outcomes for people with breast cancer and other diseases or traumatic injuries.

Purdue researchers, along with fellowship-trained breast surgeon Carla Fisher of Indiana University School of Medicine, teamed up with Purdue startup GeniPhys to develop and perform preclinical studies on a regenerative tissue filler.

This is a first-of-a-kind, in situ scaffold-forming collagen. When applied as a filler for soft tissue defects and voids, it shows promise for accelerating and improving tissue restoration outcomes. The team’s work is published in Scientific Reports.

“It would assist in maintaining the quality of life and emotional well-being of millions of breast cancer survivors each year worldwide,” said Sherry Harbin, a professor in Purdue’s Weldon School of Biomedical Engineering.

The innovators in Harbin’s lab designed and patented the collagen polymer used for this technology. A video of the technology is available here. Harbin founded GeniPhys, a Purdue startup focused on the commercialization of the collagen polymer technology.

“Such an approach may also benefit other patient populations in need of soft tissue restoration or reconstruction, including children with congenital defects, individuals with difficult-to-heal skin ulcers, individuals suffering from traumatic injuries and cancer patients requiring resection of tumors within tissues other than breast.”

A National Science Foundation SBIR Phase I award to GeniPhys supported the preclinical validation studies performed by the team, which included biomedical engineers from Purdue’s Weldon School and a fellowship-trained breast surgeon from Indiana University School of Medicine. Jeannie Plantenga and Abigail Cox from Purdue’s College of Veterinary Medicine also were part of the team.

The regenerative tissue filler, when applied to breast tissue voids, such as those associated with breast conserving surgery, restored breast shape and consistency and supported new breast tissue formation over time, including mammary glands, ducts and adipose tissue. The filler also helped avoid wound contraction and scar formation, which can be painful for patients and contribute to breast deformities.

This filler represents a highly purified liquid collagen protein, that when brought to physiologic conditions by mixing with a proprietary buffer, can be applied to tissue voids. The liquid collagen conforms to patient-specific void geometries and then undergoes a self-assembly reaction to form a fibrillar collagen scaffold like those that make up the body’s tissues.

This scaffold has soft tissue consistency and persists, where it induces a regenerative healing response.

“This tissue filler represents the first planned medical product developed using our innovative collagen polymer technology,” Harbin said. “This collagen polymer supports custom fabrication of a broad range of collagen materials for various applications including tissue restoration, therapeutic cell and drug delivery, or enhancement of tissue-implantable devices interfaces.”

Featured image: Tissue filler and scaffold technologies provide new options for patients with breast cancer and other diseases. © Purdue University

Reference: Puls, T.J., Fisher, C.S., Cox, A. et al. Regenerative tissue filler for breast conserving surgery and other soft tissue restoration and reconstruction needs. Sci Rep 11, 2711 (2021). https://www.nature.com/articles/s41598-021-81771-x?_ga=2.24305850.1447098400.1614694822-251204647.1611299879 https://doi.org/10.1038/s41598-021-81771-x

Provided by Purdue University

3-D Print Biomesh Minimizes Hernia Repair Complications (Medicine)

Hernias are one of the most common soft tissue injuries. Hernias form when intra-abdominal content, such as a loop of the intestine, squeezes through weak, defective or injured areas of the abdominal wall.

3D printed Biomesh demonstrating its mechanical strength and Flexibility © BCM

The condition may develop serious complications, therefore hernia repair may be recommended. Repair consists of surgically implanting a prosthetic mesh to support and reinforce the damaged abdominal wall and facilitate the healing process. However, currently used mesh implants are associated with potentially adverse postsurgical complications.

“Although hernia mesh implants are mechanically strong and support abdominal tissue, making the patient feel comfortable initially, it is a common problem that about three days after surgery the implant can drive inflammation that in two to three weeks will affect organs nearby,” said Dr. Crystal Shin, assistant professor of surgery at Baylor College of Medicine and lead author of this study looking to find a solution to postsurgical hernia complications.

Mesh implants mostly fail because they promote the adhesion of the intestine, liver or other visceral organs to the mesh. As the adhesions grow, the mesh shrinks and hardens, potentially leading to chronic pain, bowel obstruction, bleeding and poor quality of life. Some patients may require a second surgery to repair the unsuccessful first. “Inflammation is also a serious concern,” said Dr. Ghanashyam Acharya, associate professor of surgery at Baylor. “Currently, inflammation is controlled with medication or anti-inflammatory drugs, but these drugs also disturb the healing process because they block the migration of immune cells to the injury site.”

“To address these complications, we developed a non-pharmacological approach by designing a novel mesh that, in addition to providing mechanical support to the injury site, also acts as an inflammation modulating system,” Shin said.

Opposites attract

“A major innovation to our design is the development of a Biomesh that can reduce inflammation and, as a result, minimize tissue adhesion to the mesh that leads to pain and failure of the surgery,” Shin said.

Inflammatory mediators called cytokines appear where the mesh is implanted a few days after the surgery. Some of the main cytokines in the implant, IL1-β, IL6 and TNF-α, have a positive surface charge due to the presence of the amino acids lysine and arginine.

“We hypothesized that Biomesh with a negative surface charge would capture the positively charged cytokines, as opposite electrical charges are attracted to each other,” Acharya said. “We expected that trapping the cytokines in the mesh would reduce their inflammatory effect and improve hernia repair and the healing process.”

To test their new idea, the researchers used a 3-D-bioprinter to fabricate Biomesh of a polymer called phosphate crosslinked poly (vinyl alcohol) polymer (X-PVA). Through thorough experimentation, they optimized the mechanical properties so the mesh would withstand maximal abdominal pressure repeatedly without any deterioration of its mechanical strength for several months. They also showed that their Biomesh did not degrade or reduce its elastic properties over time and was not toxic to human cells.

Shin, Acharya and their colleagues have confirmed in the lab that this Biomesh can capture positively charged cytokines. Encouraged by these results, the researchers tested their Biomesh in a rat model of hernia repair, comparing it with a type of mesh extensively used clinically for surgical hernia repair.

Newly designed 3-D printed Biomesh minimizes postsurgical complications of hernia repair in an animal model

The newly designed Biomesh effectively minimized postsurgical complications of hernia repair in an animal model. The researchers examined the Biomesh for four weeks after it was implanted. They found that the newly designed Biomesh had captured about three times the amount of cytokines captured by the commonly used mesh. Cytokines are short-lived in the body. As they degrade, they enable the mesh to capture more cytokines.

Importantly, no visceral tissues had adhered to the newly designed Biomesh, while the level of tissue adhesion was extreme in the case of the commonly used mesh. These results confirmed that the new Biomesh is effective at reducing the effects of the inflammatory response and in preventing visceral adhesions. In addition, the new mesh did not hinder abdominal wall healing after surgical hernia repair in animal models.

“This Biomesh is unique and designed to improve outcomes and reduce acute and long-term complications and symptoms associated with hernia repair. With more than 400,000 hernia repair surgeries conducted every year in the U.S., the new Biomesh would fulfill a major unmet need,” Shin said. “There is no such multifunctional composite surgical mesh available, and development of a broadly applicable Biomesh would be a major advancement in the surgical repair of hernia and other soft tissue defects. We are conducting further preclinical studies before our approach can be translated to the clinic. Fabricating the Biomesh is highly reproducible, scalable and modifiable.”

“This concept of controlling inflammation through the physicochemical properties of the materials is new. The mesh was originally designed for mechanical strength. We asked ourselves, can we create a new kind of mesh by making use of the physical and chemical properties of materials?” said Acharya. “In the 1950s, Dr. Francis C. Usher at Baylor’s Department of Surgery developed the first polypropylene mesh for hernia repair. We have developed a next-generation mesh that not only provides mechanical support but also plays a physiological role of reducing the inflammatory response that causes significant clinical problems.” Read the complete study in the journal Advanced Materials.

Other contributors to this work include Fernando J. Cabrera, Richard Lee, John Kim, Remya Ammassam Veettil, Mahira Zaheer, Kirti Mhatre and Bradford G. Scott who are affiliated with Baylor College of Medicine. Aparna Adumbumkulath and Pulickel M. Ajayan are at Rice University and Steven A. Curley is at Christus Health Institute.

This work was supported by Baylor College of Medicine seed funding.

Current research interests of the Shin lab focus on developing broadly applicable drug delivery systems for surgical applications with enhanced therapeutic efficacy by integrating nanotechnology and 3-D bioprinting technology. She is currently working on developing controlled release nanowafer therapeutics (a hydrogel-based drug delivery system), nanodrug delivery systems for wound healing and pain management, and theranostics, a combination of therapeutics and diagnostics, for image-guided drug delivery.

Acharya’s research program focuses on the development of advanced materials for regenerative engineering by integrating nanofabrication, 3-D-nanolithography and controlled drug delivery strategies. He works at the interface of medicine, bioengineering, chemistry and pharmaceutics.

Reference: Shin, C. S., Cabrera, F. J., Lee, R., Kim, J., Ammassam, R., Zaheer, M., Adumbumkulath, A., Mhatre, K., Ajayan, P. M., Curley, S. A., Scott, B. G., Acharya, G., 3D‐Bioprinted Inflammation Modulating Polymer Scaffolds for Soft Tissue Repair. Adv. Mater. 2020, 2003778. https://doi.org/10.1002/adma.202003778 https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.202003778

Provided by Baylor College of Medicine