Tissue engineering has emerged at the intersection of numerous disciplines to meet a global clinical need for technologies to promote the regeneration of functional living tissues and organs. The complexity of many tissues and organs, coupled with confounding factors that may be associated with the injury or disease underlying the need for repair, is a challenge to traditional engineering approaches. Biomaterials, cells, and other factors are needed to design these constructs, but not all tissues are created equal. Flat tissues (skin); tubular structures (urethra); hollow, nontubular, viscus organs (vagina); and complex solid organs (liver) all present unique challenges in tissue engineering. This review highlights advances in tissue engineering technologies to enable regeneration of complex tissues and organs and to discuss how such innovative, engineered tissues can affect the clinic.

https://stm.sciencemag.org/content/scitransmed/4/160/160rv12.full.pdf

Engineering Complex Tissues

Objectives: The first tissue engineered decellularized porcine heart valve, Synergrafte (Cryolife Inc., USA) was introduced in Europe as an alternative to conventional biological valves. This is the first report of the rapid failure of these new grafts in a small series. Materials and methods: In 2001, 2 model 500 and 2 model 700 Synergrafte valves were implanted in four male children (age 2.5‐ 11 years) in the right ventricular outflow tract as a root. Two patients had a Ross operation and two had a homograft replacement. Results: The cryopreserved Synergrafte valves appeared macroscopically unremarkable at implantation. Recovery from surgery was uneventful and good valve function was demonstrated postoperatively. Three children died, two suddenly with severely degenerated Synergrafte valves 6 weeks and 1 year after implantation. The third child died on the 7th day due to Synergrafte rupture. Subsequently the fourth graft was explanted prophylactically 2 days after implantation. Macroscopically all four grafts showed severe inflammation starting on the outside (day 2 explant) leading to structural failure (day 7 explant) and severe degeneration of the leaflets and wall (6 weeks and 1 year explant). Histology demonstrated severe foreign body type reaction dominated by neutrophil granulocytes and macrophages in the early explants and a lymphocytic reaction at 1 year. In addition significant calcific deposits were demonstrated at all stages. Surprisingly pre-implant samples of the Synergrafte revealed incomplete decellularization and calcific deposits. No cell repopulation of the porcine matrix occurred. Conclusion: The xenogenic collagen matrix of the Synergrafte valve elicits a strong inflammatory response in humans which is non-specific early on and is followed by a lymphocyte response. Structural failure or rapid degeneration of the graft occurred within 1 year. Calcific deposits before implantation and incomplete decellularization may indicate manufacturing problems. The porcine Synergrafte treated heart valves should not be implanted at this stage and has been stopped. q 2003 Elsevier Science B.V. All rights reserved.

Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients.

Degradable and cell-compatible hydrogels can be designed to mimic the physical and biochemical characteristics of native extracellular matrices and provide tunability of degradation rates and related properties under physiological conditions. Hence, such hydrogels are finding widespread application in many bioengineering fields, including controlled bioactive molecule delivery, cell encapsulation for controlled three-dimensional culture, and tissue engineering. Cellular processes, such as adhesion, proliferation, spreading, migration, and differentiation, can be controlled within degradable, cell-compatible hydrogels with temporal tuning of biochemical or biophysical cues, such as growth factor presentation or hydrogel stiffness. However, thoughtful selection of hydrogel base materials, formation chemistries, and degradable moieties is necessary to achieve the appropriate level of property control and desired cellular response. In this review, hydrogel design considerations and materials for hydrogel preparation, ranging from natural polymers to synthetic polymers, are overviewed. Recent advances in chemical and physical methods to crosslink hydrogels are highlighted, as well as recent developments in controlling hydrogel degradation rates and modes of degradation. Special attention is given to spatial or temporal presentation of various biochemical and biophysical cues to modulate cell response in static (i.e., non-degradable) or dynamic (i.e., degradable) microenvironments. This review provides insight into the design of new cell-compatible, degradable hydrogels to understand and modulate cellular processes for various biomedical applications.

https://pubs.rsc.org/en/content/articlepdf/2013/cs/c3cs60040h

Designing degradable hydrogels for orthogonal control of cell microenvironments

Transdermal drug delivery offers a number of advantages for the patient, due not only its non-invasive and convenient nature, but also factors such as avoidance of first pass metabolism and prevention of gastrointestinal degradation. It has been demonstrated that microneedle arrays can increase the number of compounds amenable to transdermal delivery by penetrating the skin's protective barrier, the stratum corneum , and creating a pathway for drug permeation to the dermal tissue below. Microneedles have been extensively investigated in recent decades for drug and vaccine delivery as well as minimally invasive patient monitoring/diagnosis. This review focuses on a range of critically important aspects of microneedle technology, namely their material composition, manufacturing techniques, methods of evaluation and commercial translation to the clinic for patient benefit and economic return. Microneedle research and development is finally now at the stage where commercialisation is a realistic possibility. However, progress is still required in the areas of scaled-up manufacture and regulatory approval.

/pdf/microneedle-arrays-as-transdermal-and-intradermal-drug-2noob5nntj.pdf

Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development

This article summarizes the views expressed at the third session of the workshop "Tissue Engineering--The Next Generation," which was devoted to the engineering of complex tissue structures. Antonios Mikos described the engineering of complex oral and craniofacial tissues as a "guided interplay" between biomaterial scaffolds, growth factors, and local cell populations toward the restoration of the original architecture and function of complex tissues. Susan Herring, reviewing osteogenesis and vasculogenesis, explained that the vascular arrangement precedes and dictates the architecture of the new bone, and proposed that engineering of osseous tissues might benefit from preconstruction of an appropriate vasculature. Jennifer Elisseeff explored the formation of complex tissue structures based on the example of stratified cartilage engineered using stem cells and hydrogels. Helen Lu discussed engineering of tissue interfaces, a problem critical for biological fixation of tendons and ligaments, and the development of a new generation of fixation devices. Rita Kandel discussed the challenges related to the re-creation of the cartilage-bone interface, in the context of tissue engineered joint repair. Frederick Schoen emphasized, in the context of heart valve engineering, the need for including the requirements derived from "adult biology" of tissue remodeling and establishing reliable early predictors of success or failure of tissue engineered implants. Mehmet Toner presented a review of biopreservation techniques and stressed that a new breakthrough in this field may be necessary to meet all the needs of tissue engineering. David Mooney described systems providing temporal and spatial regulation of growth factor availability, which may find utility in virtually all tissue engineering and regeneration applications, including directed in vitro and in vivo vascularization of tissues. Anthony Atala offered a clinician's perspective for functional tissue regeneration, and discussed new biomaterials that can be used to develop new regenerative technologies.

/pdf/engineering-complex-tissues-48w7pdhn4p.pdf

Engineering complex tissues.

Polyvinyl alcohol (PVA) is a synthetic polymer derived from polyvinyl acetate through partial or full hydroxylation. PVA is commonly used in medical devices due to its low protein adsorption characteristics, biocompat- ibility, high water solubility, and chemical resistance. Some of the most common medical uses of PVA are in soft contact lenses, eye drops, embolization particles, tissue adhesion barriers, and as artificial cartilage and meniscus. The pur- pose of this review is to evaluate the available published information on PVA with respect to its safety as a medical device implant material for cartilage replacement. The review includes historical clinical use of PVA in orthopedics, and in vitro and in vivo biocompatibility studies. Finally, the safety recommendation involving the further development of PVA cryogels for cartilage replacement is addressed.

A review of polyvinyl alcohol and its uses in cartilage and orthopedic applications.

https://www.annalsthoracicsurgery.org/article/S0003-4975(01)02503-6/pdf

Decellularized human valve allografts

https://www.annalsthoracicsurgery.org/article/S0003-4975(00)01812-9/pdf

Transpecies heart valve transplant: advanced studies of a bioengineered xeno-autograft

Bioprosthetic devices (10) include an exterior biological tissue member (10-1) which at least partly defines a cavity, and a proteinaceous biopolymer (10-2) which fills the cavity, and intercalates and is chemically bound (fixed) to the tissue of the surrounding biological tissue member. In preferred forms, the bioprosthetic device (10) is a bioprosthetic vertebral disc, having a fibrillar outer annulus which surrounds and defines an interior cavity and is formed by removal of at least a substantial portion of the natural gelatinous core therefrom. The cavity defined by the fibrillar outer annulus may then be filled with a flowable proteinaceous biopolymer (10-2). Preferably, the proteinaceous biopolymer (10-2) is a liquid mixture comprised of human or animal-derived protein material and a di- or polyaldehyde, which are allowed to react in situ to form a cross-linked biopolymer within the cavity. The liquid mixture may be formed in advance of being introduced into the cavity, or may be formed simultaneously during introduction into the cavity.

In situ bioprosthetic filler and methods, particularly for the in situ formation of vertebral disc bioprosthetics

A method is provided for preparing a tissue implant for implantation. The method includes harvesting a tissue material from a human or an animal donor, treating the tissue material in a nuclease-containing solution, and thereafter treating the tissue material with an alkaline alcohol solution. The nuclease-containing solution includes an antimicrobial. The alkaline alcohol solution comprises sodium hydroxide and ethanol.

Steven P. Walsh

Papers

A review of polyvinyl alcohol and its uses in cartilage and orthopedic applications.

Decellularized human valve allografts

Transpecies heart valve transplant: advanced studies of a bioengineered xeno-autograft

In situ bioprosthetic filler and methods, particularly for the in situ formation of vertebral disc bioprosthetics

Tissue Implants for Implantation and Methods for Preparing the Same