Plastic surgical reconstruction of tissues lost from injury, infection or disease continues to evolve from the use of autologous solutions, such as skin grafts and local flaps, to the modern era of reconstructive microsurgery. An increasing range of synthetic and ‘off the shelf’ products have also been incorporated into our day-to-day care. This has provided plastic surgeons with a growing arsenal of surgical options to address a variety of functional and aesthetic needs. Synthetic implants provide a useful adjunct but can interact with the host environment in a harmful manner (silicone[1], poly[ethylene terephthalate], cellulose[2], poly[methyl methacrylate], poly[urethanes], collagen, hydroxyapatite, hydrogels [3]) through either infection, fibrosis or even rare tumors. Furthermore, implants do not mimic biological tissues and seldom resemble native tissues. Increasingly, there is a trend to opt for more biocompatible solutions.
Approximately 20 years ago, vascularized composite tissue allotransplantation (VCA) was a reconstructive milestone and deemed the best method to deliver ‘like with like’ tissue replacement. However, resourcing donor tissues remains challenging and there was the inevitable prospect of transplant rejection and immunosuppressive toxicity. Tissue engineering placed itself as a competing alternative solution since growing biological tissues donot share these same limitations. However, these technologies have been limited by scalability, integration and vascularity. As the frontier develops, we are increasingly seeing that the lasting solution will combine elements of biomaterials, cell biology, matrix biology and transplant science. One key technological enabler for this will be nanomedicine.
The application of nanotechnology in healthcare is referred to as nanomedicine and is largely responsible for the diagnosis and treatment of disease using materials on a nanoscale (one billionth of a meter). A growing body of experimental work reflects the wide variety of applications, this technology has to offer through organic (nanoemulsions, nanogels, liposomes and micelles) and inorganic nanoparticles (NPs; nanocarbons and quantum dots), 3D scaffolds and nanofibers [4]. Integrating nanomedicine, tissue engineering and engineered implants will offer a variety of solutions to fulfill even the most complex of reconstructive challenges [5]. The potential applications of these technologies in reconstructive surgery will be discussed highlighting the emerging areas where there are unmet clinical needs (Figure 1).
Modulating wounds & tissue survival through nanotechnology Nanoparticles increase the bioavailability of compounds via their large surface area-to-volume ratio. The original poly(ethylene glycol) NPs had a long shelf life, good bioavailability and nonaggregating properties, which lent itself well for drug delivery in vivo [6]. Local drug delivery by NPs can be engineered either through surface attachment [7] or encapsulation [8]. Many different NP systems have been developed or are in the process of development to influence wound care (Table 1). For example, encapsulation of morphine based NPs in dressings provides efficacious local administration of opiates directly to the wounded site [9]. Over the years, there has been anincreasing movement away from numerous drug formulations toward more advanced therapies such as incorporated specific gene therapies [10] and growth factors [11] to NPs. Furthermore, the technology can be tuneable to perform specific activities at the target site or indeed react to external stimuli such as pH, temperature[12], magnetic fields [13], ultrasound [14] or light [15], which allows for targeted affinities toward certain tissues.
In wound healing and scarring, a number of platforms exist where nanotechnologies can be employed. The topical route is favorable since therapy is directly applied to the desired site, minimizing systemic side effects. Aluminium oxide dressings incorporated through nanotopography reduces granulation tissue with maturation observed in the epidermal layers leading to improved wound healing [27]. Degradable NPs such as chitosan-based polymeric NPs (nanocrystals arising from exoskeletons of crustaceans) reportedly accelerate wound healing by regulating inflammation, fibroblast and osteoclast activity [22]. This opens up the possibility of NPs incorporating wound modulators, growth factors, antibacterial agents, analgesics and stem cells [31]. In keloid scarring for example, which is challenging to prevent or treat, keloids can be modulated using 10,11-methylenedioxycamptothecin hyaluronic acid-based nanoemulsions, as they allow better transdermal permeation than conventional creams [23].
Silver NPs are readily used in the clinical setting in numerous formulations to provide local antimicrobial therapy in a broad range of complex wounds [18]. For many years, dressings have taken advantage of silver for its role in combatting multidrug resistant bacteria. Now nanohydrogel dressings can deliver silver with minimal cytotoxicity [19]. Their success in the antimicrobial domain has influenced the use of other nanotechnologies, such as copper NPs against other organisms such as Escherichia coli, Staphylococcus aureus and fungi such as Aspergillus [20]. Copper NPs have also been shown to increase angiogenesis through modulation of HIF-1α [21] and when held within a hydrogel framework can promote the healing of diabetic wounds [32].
NP therapy, aside from being delivered locally, can be administered systemically or intravascularly for oncological control. In models for metastatic melanoma, targeted delivery of disease suppressing miRNAs 33a and 199a on a graphene oxide/oligonucleotide composite have been shown to significantly reduce tumor size in animal models [33]. These nanosized therapies enter the cells through endosomal pathways, providing an effective therapy against recurrent disease. Aside from treating tumors directly, modifying the biological activity of local tissues by genetically modified free flaps can provide disease control after tumor excision [34]. An example being tissues can be infused with lentiviral SOD2 vectors that reduces the effect of reactive oxygen species from radiotherapy damage, hence reducing vascular dysfunction, tissue distortion and fibrosis after irradiation [35]. In this way, autologous and allogeneic flaps and grafts can be engineered to suit local functional needs. This has implications in many regions where oncological adjunctive therapy results in fibrosis and contraction of tissues, namely the breast, head and neck, and gynaecological regions.
The NPs can also be used early in revascularization during free tissue transfer to mitigate ischemia reperfusion injury. Hubbell in 2004 demonstrated that NPs could minimize inflammation by acting as reactive oxygen species responsive polymers [24]. Antioxidant NPs scavenging hydrogen peroxide in ischemic rodent hind limbs show an improvement in limb survival [25]. Reduced tissue injury can also be incurred when NPs ‘block’ the infiltration of leukocytes into rodent hind limbs after reperfusion [26]. In situations where there are predictable delays or prolonged ischemia, such as an amputated limb or in tissue transplantation, the use of such scavengers could limit the damage to both the patient and tissue transferred.
In relation to VCA, NPs could play a role in immune modulation. Local delivery of immunosuppression is vital to limit off target effects and toxicity for grafts that primarily comprise of skin, the main tissue implicated in rejection. Topical NP creams in this respect, improve local sustained drug delivery [36]. The NP can be coated with a selection of modulators (antibodies, proteins, peptides and nucleic acids) [37]. Examples include targeted nanotherapies that disrupt antigen presenting cell function [38]. Tolerance may be induced by switching off immune activation using small fragments of antibodies known as nanobodies. Researchers have also taken advantage of ‘molecular camouflage’ whereby polymer chains attach to the surface of the transplanted cells enabling them to mask immune recognition [39]. Other innovations include microfabricated nanochannel membranes that interrupt T-cell signaling through gradual or timed release of immunosuppressant therapy [40] or implantable nanochips that extend drug delivery, such as rapamycin, tacrolimus and mycophenolate mofetil, from weeks to years [41]. This has particular relevance to VCA where noncompliance leads to devastating consequences; hence with these technologies, patients benefit from taking less doses and have less interference to their lifestyles [42]. The patient responsibility to comply with medication is essential for long-term success in VCA, hence simplifying this requirement for chronic therapy is essential. These technologies can be placed near or even in the VCA and tuned accordingly to minimize the systemic effects of potentially toxic therapies.
Bioimaging using nanotechnology Traditional imaging is limited by the current paucity of contrast agents giving rise to grayscale visualization in most cases. Nanoscale bioimaging, allows for a spectrum color to be used that can track multiple processes, such as inflammation, proliferation, vascularization, fibrosis, infection and early signs of tumor metastasis [43]. Quantum dots (QDot) are nanosized crystals that emit an array of colors allowing multiple donor structures to be ‘tagged’ (e.g., DNA and proteins). Physiological processes that are challenging to visualize, like lymphatic biology, can be enhanced using QDot labeling and allow for real-time evaluation of blood or lymph flow and angiogenesis in vivo. Providing visual evidence of biological activity in near real time is powerful, and nanotechnological advances are key to developing this field of human ‘molecular imaging’ [44]. These would be invaluable for decision-making and would have obvious utility in; surgical planning, dynamic imaging, monitoring tissue viability, labeling unhealthy tissue and highlighting pathological tissues, like tumor margins.
Biomimicry; tissue engineering using nanotechnology Nanomedicine has helped foster the development of biomimetic materials. These are synthetic materials designed by man to replicate one or more features of natural materials, such as functional, molecular and structural properties [45]. Tissue engineering aims to develop material scaffolds that closely resemble the structure of the natural extracellular matrix (ECM) and support a microenvironment for cell attachment, proliferation, differentiation and ultimately tissue regeneration. The most abundant ECM protein in the human body is collagen [46], present in bundles ranging between 12 nm and more than 500 nm [47,48]. To mimic this natural fibrous protein, a variety of natural macromolecules (e.g., collagen [49], silk fibrin [50] and fibrinogen [28]) and synthetic polymers (e.g., poly[glycolic acid] [29], poly[L-lactic acid] [51], poly[lactic-co-glycolic acid] [PLGA] [30] and poly[caprolactone] [PCL] [52]) have been processed using electrospinning. This technique builds scaffolds that mimic natural tissues [28–30,49–52].
Combining fiber density with the tunable stiffness of hydrogels, mechanically directs the phenotype of cell differentiation (human mesenchymal stem cell [hMSC]) by mimicking the consistency of different natural tissues (i.e., brain, muscle and bone) [53]. Engler et al. have shown that hMSC behavior toward cell morphology and differentiation was highly responsive to matrix stiffness. Indeed, hMSCs displayed morphology similar to that of neuronal cells and neurogenic expression when seeded onto the softest matrix mimicking brain tissue (Ebrain ∼0.1– 1 kPa). On tenfold stiffer matrices, myogenic differentiation of hMSCs were observed, while the substrate simulating bone (Ebone ∼25–40 kPa) directed hMSCs toward the osteoblast lineage, as cells presented polygonal shape and expressed transcriptional factors typical of mature bone cells such as osteocalcin and CBFα1 [54,55]. Hydrogels, cells and fiber biomaterials increasingly lend themselves to 3D printing and biofabrication, hence precise and clinically relevent structures are being mimicked through use of different techniques such as inkjet, microextrusion and stereolithography [56]. This tuneability through either structure, stiffness, topography or porosity encourages biocompatibility. Ultimately, the aim is to bridge the gap between human and synthetic tissue interfaces (Table 2).
Biomimicry of implants Breast augmentation is performed by plastic surgeons worldwide making breast implants the most common implant encountered in reconstructive surgery. Implant based reconstructions account for 85% of breast cancer reconstructions [57] with 1.5 million implants used worldwide in cosmetic practice (2017) [58]. One problem seen after breast augmentation is capsular contracture (17.5% of cases). This is tightening of the fibrous capsule that surrounds implants due to an exaggerated foreign body response that causes pain, a poor cosmetic result, reoperation and is the greatest cause for postoperative dissatisfaction [59,60].
Nanofunctionalization and nanotexturization represent new directions in this field (Figure 2) [61]. More recently, the development and nanotexturization of implants using photolithographical techniques has shown favorable foreign body reactions in vitro. Biomimicry at the nanoscale has been used to guide the development of these novel topographies. Acellular dermal matrix, a commercially available human derived extracellular product that has been used as an internal supportive sling in breast reconstructions, was used as a biomimetic template to generate a novel breast implant surface that improved fibroblast spread and reduced the foreign body reaction [62].
A surface produced by Barr et al. used biomimetics to recreate the close packed sphere structure of breast adipose tissue in silicone (Figure 3). Culture of macrophages and breast-derived fibroblasts, the two predominant cell types in capsular contracture showed a downregulation of pro-inflammatory cytokines IL-β1, TNF-α and IL-6 on this surface [2].
Implants primarily provide a support for the overlying breast brassiere and in recent times have become less favorable as the gold standard reconstruction after breast cancer. Further complications, such as infection, implant rupture, migration, extrusion and anaplastic large cell lymphoma (ALCL) [63,64] are some reasons autologous techniques have become more favorable. The challenge is the replacement of breast parenchyma that does not mount a reaction after implantation. This may be answered by further developments in nanotopographical engineering.
Biomimicry of soft tissues The engineering of soft tissues requires an in depth understanding of the assembly of basic structural components of tissues to mimic collagen and the ECM. For this reason, material scientists have tried to emulate the nanofibrous structure and hierarchical architecture of fibrous tissues like tendon. Techniques usually combine a biomimetic scaffold with biological factors, such as cells and growth factors to provide physical and biochemical cues for tissue growth [65].
Scaffolds obtained from decellularized sources (e.g., human [66,67], porcine[68], canine[69], bovine[70] and equine) are used; however, required donor tissues have weaker mechanical properties and are associated with a high risk of immunogenicity [71,72].
Among synthetic materials, PCL and PLGA as nanofibrous scaffolds have been widely studied. They possess high surface area-to-volume ratio, low density, high porosity, variable pore size and tuneable mechanical properties, which can mimic the highly aligned nanostructure of collagen-rich matrix in fibrous tissues. Nanofibers can be obtained using a variety of techniques. Among all, electrospinning has been widely used to produce nanofibrous scaffolds (Figure 4) [72,73]. In particular, aligned PLGA electrospun scaffold exhibiting micro- to nanofibers showed an enhanced biological response, especially under mechanical stimulation [74], which gave rise to mature collagen production by human fetal extensor tendon tenocytes and a stronger engineered construct [74]. Moreover, James et al. found that adipose-derived stem cells (ADSCs) show improved adhesion and proliferation on PLGA 3D fibrous scaffolds compared with 2D films. The electrospun 3D construct resulted in higher upregulation of scleraxis (a neotendon marker) than 2D counterparts with or without treatment with GDF-5 due to its structure that is reminiscent of tendon’s native ECM. Similarly, PCL was used in tendon tissue engineering to create biomimetic scaffolds with nanosized features that, coated with tendon-derived ECM, enhanced ADSC attachment and induced expression of tendon-specific markers [75]. Alternative studies exploited the use of electrospun yarns to more closely mimic native tendon tissue. Expression of tendon-specific markers in human ADSCs and tenocytes can be enhanced when cells were seeded on nanofiber yarn-based woven fabrics compared with random or aligned fibrous meshes [76]. The hMSCs can also undergo tendogenic differentiation on PCL electrospun yarns, with increased tensile strength and upregulation of several key fibrous genes (e.g., COL1A1) particularly under dynamic loading [77]. Many other soft tissues, like blood vessels and nerve conduits, have been engineered using this basic electrospinning platform with varying degrees of functionalization or modification of composition. Functionalization can be provided by hydroxyl, carboxyl, methyl and amine groups [78], or bioactive proteins and Arg-Gly-Asp (RGD) domains [79], or from direct surface attachment of growth factors [80].
Biomimicry of nerves Treatment after peripheral nerve injury remains purely microsurgical with either direct repair of the injured nerve endings or autologous nerve grafting where tension-free repair is not possible. Autologous nerve grafting remains the gold standard treatment in a nerve gap injury [81], providing a 3D nerve guidance scaffold with neurotrophic factors, ECM proteins and Schwann cells. The nerve fibers are enveloped within longitudinal endoneurial tubessurrounded by compression-resistant perineurium (collagen, fibronectin and laminin) and epineurium (collagenous ECM) [82,83]. Harvesting of an autologous nerve graft (ANG), however, creates a secondary nerve injury, is limited in supply and often results in a mismatch between donor and recipient nerve.
In order to address the issues of ANG harvesting, extensive research has looked into the manufacture of nerve guidance conduits that aim to replicate/mimic the ANG’s structure and function. However, their use beyond short nerve gaps is limited [84] as they are unable to promote axonal regeneration effectively over larger distances. Recent developments in bioengineering and nanomedicine have looked to evolve the smooth hollow-tube conduits into more biologically active constructs. This has involved the modification of the intraluminal surface topography of synthetic biodegradable scaffolds in order to support cellular attachment, proliferation and alignment of Schwann cells to promote axonal regeneration [85–87].
In order to replicate the endoneurial structure of the ANG, microfabrication techniques such as laser ablation or solvent casting techniques can be used to accurately produce submicrometric grooves on synthetic polymer films [88], which promote Schwann cell attachment, proliferation and cell orientation [87] leading to improved nerve regeneration in vivo [86]. These topographically enhanced synthetic polymer conduits are now being evaluated in clinical trials [89]. Electrospun polymer nano- and microfiber aligned synthetic constructs have also shown enhanced in vivo axonal regeneration [90]. Advances in electrohydrodynamic jet 3D printing have begun to tackle issues with the repeatability and scalability of electrospinning techniques while also allowing for greater precision microcustomization of the 3D constructs [91]. Gradient surface modifications of synthetic conduits with neurotrophic-enhanced hydrogels [92] show comparable in vivo nerve regeneration to syngeneic grafts. While functionalization of the 3D constructs with conductive materials such as graphene oxide has also demonstrated enhanced nerve regeneration in vivo [91,93].
Nanomedical bioengineering of the surface topography of nerve conduits and functionalization of the biomaterials used in order to mimic the autologous nerve graft has shown encouraging enhancement of nerve regeneration in animal models and has reached clinical translation. Future incorporation of neurotrophic factors, ECM proteins and supportive cells such as ADSCs converted to a Schwann cell phenotype into nerve guidance conduits show great promise for achieving similar regenerative outcomes to the ANG in longer nerve gaps (Figure 5).
Biomimicry of vasculature Vascularization represents one of the major impediments to the success of surgery necessitating implantation. This is an essential building block for tissue viability, hence is one of the most important and fundamental elements to plastic surgery. In order for cells to benefit from an adequate oxygen supply and nutrient diffusion from the vasculature, viable capillaries need to be found no more than 100–200 μm away from the cells, in both autologous [94] and engineered tissues [95]. To avoid hypoxic zones and areas of tissue necrosis, cell seeded scaffolds for tissue engineering need to quickly acquire sufficient blood supply; therefore, limiting viable engineered constructs to only thin tissues that have low metabolic demands [96]. Diffusion into these prefabricated constructs only provide a solution for short-term survival of blood vessels, hence while implantation is feasible in small animal models, results are often unsatisfactory once transplanted and tested in humans.
Nanomedicine has a role in this respect to enhance vascularization and many opportunities exist. Microspheres laden with encapsulated VEGF and angiogenin 1 promote ADSCs toward endothelial differentiation [97]. Functionalizing nanofibers with VEGF NP promote and accelerate angiogenesis of HUVECs in vitro [98], and nanoscale diamond particles can reabsorb factors like angiopoeitin 1 and VEGF and have been shown to enhance angiogenesis in chorioallantoic assays [99]. Combining any of these approaches with cell-laden technologies would enhance engineered construct angiogenesis; however, the technology could also be used to improve on outcomes of conventional surgery. Growth factors like bFGF combined with HIF-1α delivered in microcapsule formulations have been demonstrated in vivo to improve flap survival [100]. Combining these technologies with micropatterning techniques allows for considerable tunability of vascular engineering. Several engineering techniques at the microscale could be further enhanced by nanosolutions (Figure 6).
Photolithography is a micropatterning technique that uses photocrosslinked polymers in order to pattern vascular network components in 2D or 3D microenvironments. This approach utilizes a prepolymer solution that, together with an initiator, is placed under a photomask; UV radiation exposure triggers a photoreaction that crosslinks the polymer, thus forming the desired pattern [101]. The scale of the channels obtainable by this technique can now resolve to 15 μm in diameter, which is akin to capillary scale architecture [102]. Microprinting is another patterning technique that uses polymers to accurately create vascular networks within scaffolds. One strategy available is direct ink printing, which offers a very precise vascular network. Therriault et al. [103] described the use of fugitive organic ink for printing 3D vascular structures and integrating them within an epoxy matrix, providing promising results within the field [101]. This has been evolved by Wu et al. [104], who used a photocurable Pluronic F127 gel as the sacrificial ink within a hydrogel matrix. Once the sacrificial compound was removed, vascular channels remain. This technology is now sufficiently developed to produce bioprinted HUVEC-laden channels, with surrounding stromal cells [105]. The feature size that these vascular channels can achieve is 200 μm in diameter.
Microfluidics is based on the ability of closely controlling the properties and flow of fluids in a 3D scaffold. For the creation of microfluidic channels, Fidkowski et al. [106] proposed a technique that involves an initial pattern being made by inscribing a silicon wafer using micro-electro-mechanical system; the pattern is then copied on a poly(glycerol sebacate) (PGS) film and covered by a flat film in order to enclose the scaffold and form the channels. Cells can then be coated on the channels’ walls. Considering that the PGS has a high degradation rate when implanted subcutaneously [101], other polymers have also been tested with this technique, some examples including PLGA [107,108] or poly(dimethyl siloxane) [109].
Microassembly involves formation of microvascular structures that mimic the normal microarchitecture of vascular networks by directly putting together microscale hydrogels [101]. Du et al. [110] approached this technique in a study that combined microassembly with photolithography in order to create a double layered tubular structure, similar to the one of blood vessels [101]. Two concentric hydrogels were used to construct a ‘capillary’ with ‘endothelial’ and ‘smooth muscle’ layers, which was then stabilized by crosslinks formed under UV radiation. These approaches may allow the generation of small vessels; however, engineering to the capillary and lymphatic scale with the consistency and density of subsequent generations of vessels require higher resolution substrate manipulation.
Topographical cues play an important role in improving the functionality of the endothelial cells by influencing the behavior and focal adhesion expression of HUVECs [111]. Recapitulating the basement membrane nanostructure improves the affinity and aggregation of endothelial cells to the internal lumen to produce functional endothelium. Cells self-assemble in the absence of ECM signals as demonstrated by their response to silicon nanogrooves [112]. Studies with nanofibrillar films have shown that endothelial cells preferentially migrate and elongate along the pattern of nanogrooves and preferentially assemble cellular syncytiums along the patterning [113]. This property is manipulated in a number of electrospun nanofiber platforms used for microvascular tubes to form engineered vessels [114]. Nanopatterning channels on the internal and external surface of collagen scaffolds have allowed for the dual seeding of smooth muscles cells on the external surface, while allowing endothelial cell seeding on the inner surface [115]. At this scale, one could envisage technologies that involve the nanopatterning and charge of the glycocalyx to further enhance the antithrombotic nanostructure of vessels [116,117].
Biomimetic hard tissues
The engineering of cartilage and bone represents a thriving area of nanotechnology. In part, this is driven by the wealth of biocompatible stiff materials and the possibility to tune their physical, chemical and structural properties to mimic the many nanofeatures of cartilage and bone matrices.
Since the 1990s, a wide range of biomaterials have been exploited for cartilage and bone applications, but more recently the usage of hydrogels has received particular interest due to their network of interacting hydrophilic polymer chains that presents many similarities with the native tissue ECM [118]. In articular cartilage substitution, hydrogels represent valuable substrate as they enhance chondrocyte adhesion [119] maintain cell phenotype [120] and provide mechanical support with their viscoelastic properties [121]. On the other side, in bone repair, hydrogels provide a network that strongly integrates with the natural ECM, while encapsulating bioactive molecules that can be released from the substrate as required [122]. More recently, injectable hydrogels have been investigated as they can be delivered at the injury site with minimal invasiveness and adjust themselves to match the irregular shape of the defect [118]. For example, injectable dextran-based hydrogels, which can be modified to rapidly assemble into crosslinked bioscaffolds, were used with chondrocytes for cartilage applications [123]. Authors showed that both individual chondrocytes and chondrocyte spheroids produced cartilaginous matrix, and the hydrogel properties can be easily tuned by controlling polymer concentration and substitution of the dextran conjugates [123]. For bone tissue engineering, osteoinductive and osteoconductive super paramagnetic Fe3O4 NPs and hydroxyapatite NPs have been incorporated in a thermo-responsive injectable hydrogel, showing modulation of the bone biomarkers and improved construct mineralization. Functionalization and stronger mechanical properties can also be attained by incorporating graphene oxide, which when combined with conventional hydrogels, develops stronger mechanical characteristics, healthier tissues and provides the versatility to obtain bioprintable hydrogels [124].
In bone, many NPs can be inductors of osteogenesis, such as nanohydroxyapaptite [125] and graphene oxide [126]. Nanomedicine incorporation into bone substitutes not only provides an opportunity to deliver therapies but also facilitates the development of the nanotopology that is favorable for osseointegration. Graphene oxide can also be incorporated into biocomposites of bone and can promote the differentiation of stem cells toward and osteoinduction without the addition of growth factors [127]. As NPs can be composed of ceramics, hydroxyapatites, carbon nanotubes and metal composites, they are particularly strong, and compatible with osteointegration. Chitosan-based NPs can also provide slow release of antimicrobial formulations [128] or be proregenerative [129] depending on the moieties attached.
Combining both bone and cartilage regenerative therapies allows for the engineering of osteochondral materials, which is seen as the more reliable method for cartilage replacement due to delamination of engineered cartilage on extremes of sheer [130]. These nanoengineered composite materials incorporate bioactive scaffolds, nanofibers and act as an eluting nanoreservoir for growth factors that maintain the local cellular populations such as MSCs [131].
Future perspective/application toward the clinic
A wide variety of nanotechnologies have been highlighted that could be developed to aid reconstructive surgery, from targeted drug therapy, diagnostic imaging, through to complex tissue engineering.
Nanotechnology in general is the new enabler of therapies, allowing previous biological barriers to be overcome. It is likely that areas such as bioimaging and cancer therapy represent the areas in which nanotechnology will impact reconstructive surgery first, as these areas are already advanced in other clinical specialities, and specifically have transient, if any toxicity, or are designed to be toxic to targeted cells [132,133]. We will see the repurposing of old technologies, like growth factor therapies using nanotechnology for more efficacious delivery. Nanotopology and biomimicry of engineered tissues is still several years off clinical application as long-term safety studies will need to be shown before they can be used in tissue replacement. Key to the adoption of tissue engineered therapies to clinical practice will be the the ability to incorporate these engineered tissues into our current clinical skill set.
Developing platforms that utilize our microsurgical and transplantation skills would encourage interest from many plastic surgeons and aid in the potential translation of these technologies. Simple surgical technologies like the arteriovenous loop described [134], and the subsequent pioneering work by Morrison’s group [135] on vascularization serves as platform that could ultimately be used to harness the potential of biomimetic tissues. Indeed, many researchers have used the platform to engineer soft tissues [136] organs [137] and bone [138]; however, the cross over to patient benefit has not been successful. This could change with nanotechnology as an enabler.
At present, the likely impact on reconstructive practice is still theoretical, and the success of adoption will depend largely on the demonstration of safety in human scale models. Indeed, the NP technology may have harmful long-term biological effects that are yet to be described. Aggregation of nanoparticles in tissues leading to fibrosis, organ dysfunction, genetic alterations of cells and autoimmune disease are all potential off target side effects that will need to be monitored for carefully in future clinical applications [139,140]. Studies suggest that nanoscale technologies are no more dangerous than conventional drug therapies or materials, although regulation and study of their toxicology has specific challenges [141]. The retention of NPs in the interstitium of murine hind limb muscle for 21 days has been reported, yet authors question the localized effects and the degree of toxicity in human studies indicating that large animal studies are needed. Further, the biodistribution of these agents has come under scrutiny since there are complex reactions within the host, which are not fully understood, and may well lead to off target effects [142]. Advanced models for testing biocompatible safety may require more intricate systems than standard in vivo models. Wheras porcine in vivo models are usually used to evaluate the safety of nanopharmaceuticals [143], machine perfusion (MP) on porcine tissues may be a more accurate way to assess the distribution and cellular activity of these therapies in a more controllable fashion [144]. The successful preservation of human cadaver limbs using a blood-based medium supports the role of MP in translational testing and delivering nanotherapies by this approach, evaluating the systemic effects without harming patients [145]. Other approaches could be to test NPs using multiple interlinked organs on chips, and would provide some insight into how nanoscale therapies interact with different tissue types [146]
Few trials are actively recruiting for the application of nanotechnology in reconstructive surgery. Clinical trials using nanotechnology with relevance to plastic surgery include studies examining the use of nanoluteolin (chemotherapeutic) as a vehicle to induce apoptosis in squamous cell carcinoma (NCT03288298). Recruitment has also completed in two studies attempting to evaluate the efficacy of topical nanocapsule anesthesia. One performed in those undergoing CO2 fractional laser, frequently used by dermatologists and plastic surgeons (NCT03366246), and similarly another trial monitoring plasma concentrations of nanodelivered lidocaine and prilocaine. Buckypaper derived from Buckminsterfullerene is registered to trial its adhesive properties with prosthetic materials such as prosthetic mesh (NCT02137018). Fullerenes also have extended their use in the lab to growing biological tissues including nerve cells and muscle. This illustrates that we are still at the very beginning of identifying the potential applications for nanotherapies in reconstructive surgery.
The benefits offered by nanotechnologies toward enhancing biological processes, promoting better biomaterial compatibility and generating functionalized tissues are exciting opportunities and show great potential. The appliance of nanotech is still in its infancy, but in all likelihood will play a significant role in continuing innovation within the specialty of plastic and reconstructive surgery.
Executive summary
• Within the breadth of plastic and reconstructive surgery, there are many avenues where nanotechnology will inevitably have an impact ranging from bioimaging through to tissue engineering.
• Early applications of nanotechnology will be in topical therapies, novel dressings and molecular imaging. Efficacy has already been demonstrated in the cancer fields.
• An increasing trend of nanotechnology applications will find there way into developing new biomimetic tissues and smart materials that will be used in the armamentarium for replacement parts in reconstructive surgery.
• Both soft (skin, tendons, nerves and vasculature) and hard tissues (cartilage and bone) are being catered for in the engineering, and enhanced treatment of damaged tissues using nanotechnology approaches.
• Novel nanotherapy approaches are being trialed to enhance the properties of the tissues used for reconstruction and potentially have applications in reducing complex processes like fibrosis, tumor recurrence and immune tolerance.
• Awareness of these advances for plastic surgeons will be important for the adoption and incorporation of these therapies into clinical care and potentially opens up new frontiers in surgical innovation.
Author contributions Each author has contributed to the written text. In addition, experts in their field have provided a summary of their experimental work of relevance.
Financial & competing interests disclosure K Amin, A Imere and R Murphy were funded by the EPSRC/MRC Centre for Doctoral Training in Regenerative Medicine. K Amin was also funded by a one year Royal College of Surgeons of England Fellowship and British Society of Surgery of the Hand one year fellowship. A Reid is funded by NIHR I4I award (grant number IILA0313 20003). J Wong is funded by a Versus Arthritis Award (grant number 22032) and Royal College of Surgeons of Edinburgh Small Support Award (grant number SPPG/18/120). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Open access This work is licensed under the Creative Commons Attribution4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
References Papers of special note have been highlighted as: • of interest; •• of considerable interest
1. Barr S, Bayat A. Breast implant surface development: perspectives on development and manufacture. Aesthet. Surg. J. 31(1), 56–67 (2011).
2. Barr S, Hill EW, Bayat A. Development, fabrication and evaluation of a novel biomimetic human breast tissue derived breast implant surface. Acta Biomaterialia 49, 260–271 (2017).
• This paper from one of our authors highlights one of the earlier applications of nanotopography for better biocompatibility.
3. Mishra M. Encyclopedia of Polymer Applications, 3 Volume Set. Taylor & Francis Group, FL, USA (2018).
4. Shi J, Votruba AR, Farokhzad OC, Langer R. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 10(9), 3223–3230 (2010).
5. Van Rijt S, Habibovic P. Enhancing regenerative approaches with nanoparticles. J. R. Soc. Interface 14(129), 1–10 (2017).
6. Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R. Biodegradable long-circulating polymeric nanospheres. Science 263(5153), 1600–1603 (1994).
7. Choi SW, Kim WS, Kim JH. Surface modification of functional nanoparticles for controlled drug delivery. J. Dispers. Sci. Technol. 24(3-4), 475–487 (2003).
8. Suk KH, Gopinath SCB. Drug encapsulated nanoparticles for treating targeted cells. Curr. Med. Chem. 24(30), 3310–3321 (2017).
9. Kuchler S, Wolf NB, Heilmann S et al. 3D-wound healing model: influence of morphine and solid lipid nanoparticles. J. Biotechnol.148(1), 24–30 (2010).
10. Majidi S, Zeinali Sehrig F, Samiei M et al. Magnetic nanoparticles: applications in gene delivery and gene therapy. Artif. Cells Nanomed. Biotechnol. 44(4), 1186–1193 (2016).
11. Chen Y, Wu Y, Gao J et al. Transdermal vascular endothelial growth factor delivery with surface engineered gold nanoparticles. ACS Appl. Mater. Interfaces 9(6), 5173–5180 (2017).
12. Zhao Y, Shi C, Yang X et al. pH- and temperature-sensitive hydrogel nanoparticles with dual photoluminescence for bioprobes. ACS Nano 10(6), 5856–5863 (2016).
13. Alvizo-Baez CA, Luna-Cruz IE, Vilches-Cisneros N, Rodriguez-Padilla C, Alcocer-Gonzalez JM. Systemic delivery and activation of the TRAIL gene in lungs, with magnetic nanoparticles of chitosan controlled by an external magnetic field. Int. J. Nanomed. 11, 6449–6458 (2016).
14. Kost J, Leong K, Langer R. Ultrasound-enhanced polymer degradation and release of incorporated substances. Proc. Natl Acad. Sci. USA 86(20), 7663–7666 (1989).
15. Afkhami F, Akbari S, Chiniforush N. Entrococcus faecalis elimination in root canals using silver nanoparticles, photodynamic therapy, diode laser, or laser-activated nanoparticles: an in vitro study. J. Endod. 43(2), 279–282 (2017).
16. Yang Q, Lai SK. Engineering well-characterized PEG-coated nanoparticles for elucidating biological barriers to drug delivery. Methods Mol. Biol.1530, 125–137 (2017).
17. Yang J, Hao X, Li Q et al. CAGW peptide- and PEG-modified gene carrier for selective gene delivery and promotion of angiogenesis in HUVECs in vivo. ACS Appl. Mater. Interfaces 9(5), 4485–4497 (2017).
18. Wilkinson LJ, White RJ, Chipman JK. Silver and nanoparticles of silver in wound dressings: a review of efficacy and safety. J. Wound Care 20(11), 543–549 (2011).
19. Adhya A, Bain J, Ray O et al. Healing of burn wounds by topical treatment: a randomized controlled comparison between silver sulfadiazine and nano-crystalline silver. J. Basic Clin. Pharm. 6(1), 29–34 (2014).
20. Ramyadevi J, Jeyasubramanian K, Marikani A, Rajakumar G, Rahuman AA. Synthesis and antimicrobial activity of copper nanoparticles. Mater. Lett. 71, 114–116 (2012).
21. Zhang Z, Qiu L, Lin C et al. Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression. Metallomics 6(10), 1889–1893 (2014).
22. Baxter RM, Dai T, Kimball J et al. Chitosan dressing promotes healing in third degree burns in mice: gene expression analysis shows biphasic effects for rapid tissue regeneration and decreased fibrotic signaling. J. Biomed. Mater. Res. A101(2), 340–348 (2013).
23. Gao Y, Cheng X, Wang Z et al. Transdermal delivery of 10,11-methylenedioxycamptothecin by hyaluronic acid based nanoemulsion for inhibition of keloid fibroblast. Carbohydr. Polym.112, 376–386 (2014).
24. Napoli A, Valentini M, Tirelli N, Muller M, Hubbell JA. Oxidation-responsive polymeric vesicles. Nat. Mater. 3(3), 183–189 (2004).
25. Lee D, Bae S, Ke Q et al. Hydrogen peroxide-responsive copolyoxalate nanoparticles for detection and therapy of ischemia-reperfusion injury. J. Control. Rel.172(3), 1102–1110 (2013).
26. Kamaly N, Fredman G, Subramanian M et al. Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles. Proc. Natl Acad. Sci. USA 110(16), 6506–6511 (2013).
27. Parkinson LG, Rea SM, Stevenson AW, Wood FM, Fear MW. The effect of nano-scale topography on keratinocyte phenotype and wound healing following burn injury. Tissue Eng. Part A 18(7–8), 703–714 (2012).
28. Wnek GE, Carr ME, Simpson DG, Bowlin GL. Electrospinning of nanofiber fibrinogen structures. Nano Lett. 3(2), 213–216 (2003).
29. Boland ED, Wnek GE, Simpson DG, Pawlowski KJ, Bowlin GL. Tailoring tissue engineering scaffolds using electrostatic processing techniques: a study of poly(glycolic acid) electrospinning. J. Macromol. Sci. Part A 38(12), 1231–1243 (2001).
30. Li WJ, Laurencin CT, Caterson EJ, Tuan RS, Ko FK. Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J. Biomed. Mater. Res. 60(4), 613–621 (2002).
31. Ahmed EM. Hydrogel: preparation, characterization, and applications: a review. J. Adv. Res.6(2), 105–121 (2015).
32. Xiao J, Chen S, Yi J, Zhang H, Ameer GA. A cooperative copper metal-organic framework-hydrogel system improves wound healing in diabetes. Adv. Funct. Mater. 27(1), 1–21 (2017).
33. Liu C, Xie H, Yu J et al. A targeted therapy for melanoma by graphene oxide composite with microRNA carrier. Drug Des. Devel. Ther. 12, 3095–3106 (2018).
•• Shows the impressive in vivo effect of combining nanocarriers with olignonucleotide technology with miRNAs specific against melanoma, showing a real impact on tumor development. Highlights how combining the technologies enhances the therapy well.
34. Seth R, Khan AA, Pencavel T, Harrington KJ, Harris PA. Targeted gene delivery by free-tissue transfer in oncoplastic reconstruction. Lancet Oncol. 13(9), e392–e402 (2012).
• A good review on the value of pretreatment of free flaps to potential being resistant or therapeutic back on the recipient site.
35. Khan AA, Paget JT, McLaughlin M et al. Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues. Sci. Transl. Med. 10(425), 1–14 (2018).
36. Feturi FG, Weinstock M, Zhao W et al. Mycophenolic acid for topical immunosuppression in vascularized composite allotransplantation: optimizing formulation and preliminary evaluation of bioavailability and pharmacokinetics. Front. Surg. 5, 20 (2018).
37. Lavan DA, McGuire T, Langer R. Small-scale systems for in vivo drug delivery. Nat. Biotechnol. 21(10), 1184–1191 (2003).
38. Kaplan B, Burckart JG, Lakkis GF. Immunotherapy in Transplantation: Principles and Practice. Wiley-Blackwell, Chichester, UK, 14–15 (2012).
39. M Samarasinghe R, K Kanwar R, R Kanwar J. The role of nanomedicine in cell based therapeutics in cancer and inflammation. Int. J. Mol. Cell. Med.1(3), 133–144 (2012).
40. Sakamoto JH, Van De Ven AL, Godin B et al. Enabling individualized therapy through nanotechnology. Pharmacol. Res. 62(2), 57–89 (2010).
41. Ochando J, Braza MS. Nanoparticle-based modulation and monitoring of antigen-presenting cells in organ transplantation. Front. Immunol. 8, 1888 (2017).
42. Kumnig M, Jowsey-Gregoire SG. Key psychosocial challenges in vascularized composite allotransplantation. World J. Transplant. 6(1), 91–102 (2016).
43. Gonda K, Watanabe TM, Ohuchi N, Higuchi H. In vivo nano-imaging of membrane dynamics in metastatic tumor cells using quantum dots. J. Biol. Chem. 285(4), 2750–2757 (2010).
44. Andreou C, Pal S, Rotter L, Yang J, Kircher MF. Molecular imaging in nanotechnology and theranostics. Mol. Imaging Biol.19(3), 363–372 (2017).
45. Glaser DE, Viney C. Chapter 1.2.18 Biomimetric materials. In: Biomaterials Science: An Introduction to Materials in Medicine (3rd Edition). Ratner BD, Hoffman AS, Schoen FJ, Lemons J (Eds). Elsevier Oxford, UK, 349–359 (2012).
46. Ma PX. Biomimetic materials for tissue engineering. Adv. Drug Deliv. Rev. 60(2), 184–198 (2008).
47. Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv. Drug Deliv. Rev. 97, 4–27 (2016).
48. Kadler KE, Baldock C, Bella J, Boot-Handford RP. Collagens at a glance. J. Cell Sci. 120(Pt 12), 1955–1958 (2007).
49. Matthews JA, Wnek GE, Simpson DG, Bowlin GL. Electrospinning of collagen nanofibers. Biomacromolecules 3(2), 232–238 (2002).
50. Li C, Vepari C, Jin HJ, Kim HJ, Kaplan DL. Electrospun silk-BMP-2 scaffolds for bone tissue engineering. Biomaterials 27(16), 3115–3124 (2006).
51. Yang F, Murugan R, Wang S, Ramakrishna S. Electrospinning of nano/micro scale poly(L-lactic acid) aligned fibers and their potential in neural tissue engineering. Biomaterials 26(15), 2603–2610 (2005).
52. Yoshimoto H, Shin YM, Terai H, Vacanti JP. A biodegradable nanofiber scaffold by electrospinning and its potential for bone tissue engineering. Biomaterials 24(12), 2077–2082 (2003).
53. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 126(4), 677–689 (2006).
•• Key paper on understanding how mechanical properties of materials can influence cellular behavior and phenotype.
54. Wen JH, Vincent LG, Fuhrmann A et al. Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat. Mater.13(10), 979–987 (2014).
55. Eroshenko N, Ramachandran R, Yadavalli VK, Rao RR. Effect of substrate stiffness on early human embryonic stem cell differentiation. J. Biol. Eng. 7(1), 7 (2013).
56. Bishop ES, Mostafa S, Pakvasa M et al. 3-D bioprinting technologies in tissue engineering and regenerative medicine: current and future trends. Genes Dis. 4(4), 185–195 (2017).
57. Leff DR, Bottle A, Mayer E et al. Trends in immediate postmastectomy breast reconstruction in the United Kingdom. Plast. Reconstr. Surg. Glob. Open 3(9), e507 (2015).
58. Surgery ISOaP. ISAPS Global Statistics. (2017).
59. Handel N, Cordray T, Gutierrez J, Jensen JA. A long-term study of outcomes, complications, and patient satisfaction with breast implants. Plastic Reconstr. Surg. 117(3), 757–767 (2006).
60. Gabriel SE, Woods JE, O’Fallon WM, Beard CM, Kurland LT, Melton LJ. Complications leading to surgery after breast implantation. N. Engl. J. Med. 336(10), 677–682 (1997).
61. Grandview. Breast implants market size worth $2.0billion by 2025 (2018). www.grandviewresearch.com/industry-analysis/breastimplants-market?utm source=google&utm medium=cpc&utm campaign=AdWords Breast-ImplantsMarket Type1 Healthcare&gclid=Cj0KCQjwwb3rBRDrARIsALR3XeaPsONIz1fi5aUns8UYCwY qmIyMH1 sZm2837oJKVhWRXzkf8lffcaAswxEALw wcB
62. Kyle DJ, Oikonomou A, Hill E, Bayat A. Development and functional evaluation of biomimetic silicone surfaces with hierarchical micro/nano-topographical features demonstrates favourable in vitro foreign body response of breast-derived fibroblasts. Biomaterials 52, 88–102 (2015).
63. Vu K, Ai W. Update on the treatment of anaplastic large cell lymphoma. Curr. Hematol. Malig. Rep.13(2), 135–141 (2018).
64. Dixon JM, Clemens M. Breast implants and anaplastic large cell lymphoma. BMJ 363, k5054 (2018). 65. Ramos D, Peach MS, Mazzocca AD, Yu X, Kumbar SG. Chapter 8: Tendon tissue engineering. In: Regenerative Engineering of Musculoskeletal Tissues and Interfaces. Nukavarapu SP, Freeman JW, Laurencin C (Eds). Woodhead Publishing, Cambridge, UK, 195–217 (2015).
66. Martinello T, Bronzini I, Volpin A et al. Successful recellularization of human tendon scaffolds using adipose-derived mesenchymal stem cells and collagen gel. J. Tissue Eng. Med. 8(8), 612–619 (2014).
67. Raghavan SS, Woon CY, Kraus A et al. Human flexor tendon tissue engineering: decellularization of human flexor tendons reduces immunogenicity in vivo. Tissue Eng. Part A 18(7–8), 796–805 (2012).
68. Seyler TM, Bracey DN, Plate JF et al. The development of a xenograft-derived scaffold for tendon and ligament reconstruction using a decellularization and oxidation protocol. Arthroscopy 33(2), 374–386 (2017).
69. Ozasa Y, Amadio PC, Thoreson AR, An KN, Zhao C. The effect of surface modification on gliding ability of decellularized flexor tendon in a canine model in vitro. J. Hand Surg. Am. 38(9), 1698–1704 (2013).
70. Zhang CH, Jiang YL, Ning LJ et al. Evaluation of decellularized bovine tendon sheets for achilles tendon defect reconstruction in a rabbit model. Am. J. Sports Med. 46(11), 2687–2699 (2018).
71. Lovati AB, Bottagisio M, Moretti M. Decellularized and engineered tendons as biological substitutes: a critical review. Stem Cells Int. 2016, 7276150 (2016).
72. Zhang X, Bogdanowicz D, Erisken C, Lee NM, Lu HH. Biomimetic scaffold design for functional and integrative tendon repair. J. Shoulder Elbow Surg. 21(2), 266–277 (2012).
73. Lomas AJ, Ryan CN, Sorushanova A et al. The past, present and future in scaffold-based tendon treatments. Adv. Drug Deliv. Rev. 84, 257–277 (2015).
74. Wang B, Liu W, Zhang Y et al. Engineering of extensor tendon complex by an ex vivo approach. Biomaterials 29(20), 2954–2961 (2008).
75. Chainani A, Hippensteel KJ, Kishan A et al. Multilayered electrospun scaffolds for tendon tissue engineering. Tissue Eng. Part A 19(23–24), 2594–2604 (2013).
76. Wu S, Wang Y, Streubel PN, Duan B. Living nanofiber yarn-based woven biotextiles for tendon tissue engineering using cell tri-culture and mechanical stimulation. Acta Biomater. 62, 102–115 (2017).
77. Bosworth LA, Rathbone SR, Bradley RS, Cartmell SH. Dynamic loading of electrospun yarns guides mesenchymal stem cells towards a tendon lineage. J. Mech. Behav. Biomed. Mater. 39, 175–183 (2014).
78. Thevenot P, Hu W, Tang L. Surface chemistry influences implant biocompatibility. Curr. Top. Med. Chem. 8(4), 270–280 (2008).
79. Zhu R, Tian Y. Preparation and evaluation of RGD and TAT co-modified docetaxel-loaded liposome. Drug Des. Devel. Ther. 11, 3481–3489 (2017).
80. Pauly HM, Sathy BN, Olvera D et al. * Hierarchically structured electrospun scaffolds with chemically conjugated growth factor for ligament tissue engineering. Tissue Eng. Part A 23(15–16), 823–836 (2017).
81. Millesi H. Bridging defects: autologous nerve grafts. Acta Neurochir. Suppl. 100, 37–38 (2007).
82. Peltonen S, Alanne M, Peltonen J. Barriers of the peripheral nerve. Tissue Barriers 1(3), e24956-1–e24956-6 (2013).
83. Pina-Oviedo S, Ortiz-Hidalgo C. The normal and neoplastic perineurium: a review. Adv. Anat. Pathol. 15(3), 147–164 (2008).
84. Pabari A, Lloyd-Hughes H, Seifalian AM, Mosahebi A. Nerve conduits for peripheral nerve surgery. Plast. Reconstr. Surg. 133(6), 1420–1430 (2014).
85. Faroni A, Mobasseri SA, Kingham PJ, Reid AJ. Peripheral nerve regeneration: experimental strategies and future perspectives. Adv. Drug Deliv. Rev. 82–83, 160–167 (2015).
86. Mobasseri A, Faroni A, Minogue BM, Downes S, Terenghi G, Reid AJ. Polymer scaffolds with preferential parallel grooves enhance nerve regeneration. Tissue Eng. Part A 21(5–6), 1152–1162 (2015).
87. Sun M, McGowan M, Kingham PJ, Terenghi G, Downes S. Novel thin-walled nerve conduit with microgrooved surface patterns for enhanced peripheral nerve repair. J. Mater. Sci. Mater. Med. 21(10), 2765–2774 (2010).
88. Curtis A, Wilkinson C. Topographical control of cells. Biomaterials 18(24), 1573–1583 (1997).
89. ClinicalTrials.gov. A Phase I trial of a novel synthetic polymer nerve conduit “polynerve” in participants with sensory digital nerve injury. (2019) https://clinicaltrials.gov/ct2/show/NCT02970864
90. Kim YT, Haftel VK, Kumar S, Bellamkonda RV. The role of aligned polymer fiber-based constructs in the bridging of long peripheral nerve gaps. Biomaterials 29(21), 3117–3127 (2008).
91. Vijayavenkataraman S, Zhang S, Thaharah S, Sriram G, Lu WF, Fuh JYH. Electrohydrodynamic jet 3D printed nerve guide conduits (NGCs) for peripheral nerve injury repair. Polymers (Basel) 10(7), e753-1-25 (2018).
92. Dodla MC, Bellamkonda RV. Differences between the effect of anisotropic and isotropic laminin and nerve growth factor presenting scaffolds on nerve regeneration across long peripheral nerve gaps. Biomaterials 29(1), 33–46 (2008).
93. Vijayavenkataraman S, Thaharah S, Zhang S, Lu WF, Fuh JYH. Electrohydrodynamic jet 3D-printed PCL/PAA conductive scaffolds with tunable biodegradability as nerve guide conduits (NGCs) for peripheral nerve injury repair. Mater. Design 162, 171–184 (2019).
94. Rouwkema J, Rivron NC, Van Blitterswijk CA. Vascularization in tissue engineering. Trends Biotech. 26(8), 434–441 (2008).
95. Zisch AH, Lutolf MP, Hubbell JA. Biopolymeric delivery matrices for angiogenic growth factors. Cardiovas. Pathol. 12(6), 295–310 (2003).
96. Morrison WA, Marre D, Grinsell D, Batty A, Trost N, O’Connor AJ. Creation of a large adipose tissue construct in humans using a tissue-engineering chamber: a step forward in the clinical application of soft tissue engineering. EBioMedicine 6, 238–245 (2016).
97. He Y, Li Z, Chen Z et al. Effects of VEGF-ANG-1-PLA nano-sustained release microspheres on proliferation and differentiation of ADSCs. Cell. Biol. Int. 42(8), 1060–1068 (2018).
98. Wagner Q, Offner D, Idoux-Gillet Y et al. Advanced nanostructured medical device combining mesenchymal cells and VEGF nanoparticles for enhanced engineered tissue vascularization. Nanomedicine (Lond.) 11(18), 2419–2430 (2016).
99. Schimke MM, Stigler R, Wu X et al. Biofunctionalization of scaffold material with nano-scaled diamond particles physisorbed with angiogenic factors enhances vessel growth after implantation. Nanomedicine 12(3), 823–833 (2016).
100. Chen GJ, Chen YH, Yang XQ, Li ZJ. Nano-microcapsule basic fibroblast growth factor combined with hypoxia-inducible factor-1 improves random skin flap survival in rats. Mol. Med. Rep.13(2), 1661–1666 (2016).
101. Peak CW, Cross L, Microscale technologies for engineering complex tissue structures. In: Microscale Technologies for Cell Engineering. Singh A, Gaharwar AK (Eds). Springer International Publishing, Cham, Switerland, 3–25 (2016).
102. Gallab M, Tomita K, Omata S, Arai F. Fabrication of 3D capillary vessel models with circulatory connection ports. Micromachines (Basel) 9(3), E101 (2018).
103. Therriault D, White SR, Lewis JA. Chaotic mixing in three-dimensional microvascular networks fabricated by direct-write assembly. Nat. Mater. 2(4), 265–271 (2003).
104. Wu W, Deconinck A, Lewis JA. Omnidirectional printing of 3D microvascular networks. Adv. Mater. 23(24), 178–183 (2011).
105. Kolesky DB, Homan KA, Skylar-Scott MA, Lewis JA. Three-dimensional bioprinting of thick vascularized tissues. Proc. Natl Acad. Sci. USA 113(12), 3179–3184 (2016).
•• Considerable breakthrough in bioprinting functional vascular networks.
106. Fidkowski C, Kaazempur-Mofrad MR, Borenstein J, Vacanti JP, Langer R, Wang Y. Endothelialized microvasculature based on a biodegradable elastomer. Tissue Eng. 11(1–2), 302–309 (2005).
107. Armani DK, Liu C. Microfabrication technology for polycaprolactone, a biodegradable polymer. J. Micromech. Microeng. 10(1), 80–84 (2000).
108. King KR, Wang CCJ, Kaazempur-Mofrad MR, Vacanti JP, Borenstein JT. Biodegradable microfluidics. Adv. Mater. 16(22), 2007–2012 (2004).
109. Borenstein JT, Terai H, King KR, Weinberg EJ, Kaazempur-Mofrad MR, Vacanti JPJBM. Microfabrication technology for vascularized tissue engineering. Biomed. Microdevices. 4(3), 167–175 (2002).
110. Du Y, Ghodousi M, Qi H, Haas N, Xiao W, Khademhosseini A. Sequential assembly of cell-laden hydrogel constructs to engineer vascular-like microchannels. Biotechnol. Bioeng.108(7), 1693–1703 (2011).
111. Chong DS, Turner LA, Gadegaard N, Seifalian AM, Dalby MJ, Hamilton G. Nanotopography and plasma treatment: redesigning the surface for vascular graft endothelialisation. Eur. J. Vasc. Endovasc. Surg. 49(3), 335–343 (2015).
112. Dreier B, Gasiorowski JZ, Morgan JT, Nealey PF, Russell P, Murphy CJ. Early responses of vascular endothelial cells to topographic cues. Am. J. Physiol. Cell Physiol. 305(3), C290–C298 (2013).
113. Nakayama KH, Surya VN, Gole M et al. Nanoscale patterning of extracellular matrix alters endothelial function under shear stress. Nano Lett. 16(1), 410–419 (2016).
114. Moffa M, Sciancalepore AG, Passione LG, Pisignano D. Combined nano- and micro-scale topographic cues for engineered vascular constructs by electrospinning and imprinted micro-patterns. Small 10(12), 2439–2450 (2014).
115. Zorlutuna P, Vadgama P, Hasirci V. Both sides nanopatterned tubular collagen scaffolds as tissue-engineered vascular grafts. J. Tissue Eng. Regen. Med. 4(8), 628–637 (2010).
116. Khosravi A, Shirazi HA, Asnafi A, Karimi A. A fully analytical approach to investigate the electro-viscous effect of the endothelial glycocalyx layer on the microvascular blood flow. Clin. Chim. Acta 472, 5–12 (2017).
117. Zamani M, Khafaji M, Naji M, Vossoughi M, Alemzadeh I, Haghighipour N. A biomimetic heparinized composite silk-based vascular scaffold with sustained antithrombogenicity. Sci. Rep. 7(1), 4455 (2017).
118. Liu M, Zeng X, Ma C et al. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res. 5, 17014 (2017 ).
119. Cushing MC, Anseth KS. Materials science. Hydrogel cell cultures. Science 316(5828), 1133–1134 (2007).
120. Yamaoka H, Asato H, Ogasawara T et al. Cartilage tissue engineering using human auricular chondrocytes embedded in different hydrogel materials. J. Biomed. Mater. Res. A 78(1), 1–11 (2006).
121. Mauck RL, Soltz MA, Wang CC et al. Functional tissue engineering of articular cartilage through dynamic loading of chondrocyte-seeded agarose gels. J. Biomech. Eng.
122(3), 252–260 (2000). 122. Wu G, Feng C, Quan J et al. In situ controlled release of stromal cell-derived factor-1alpha and antimiR-138 for on-demand cranial bone regeneration. Carbohydr. Polym.182, 215–224 (2018).
123. Wang X, Li Z, Shi T et al. Injectable dextran hydrogels fabricated by metal-free click chemistry for cartilage tissue engineering. Mater. Sci. Eng. C Mater. Biol. Appl. 73, 21–30 (2017).
124. Cheng Z, Landish B, Chi Z et al. 3D printing hydrogel with graphene oxide is functional in cartilage protection by influencing the signal pathway of Rank/Rankl/OPG. Mater. Sci. Eng. C Mater. Biol. Appl. 82, 244–252 (2018).
125. Chu C, Deng J, Man Y, Qu Y. Evaluation of nanohydroxyapaptite (nano-HA) coated epigallocatechin-3-gallate (EGCG) cross-linked collagen membranes. Mater. Sci. Eng. C Mater. Biol. Appl. 78, 258–264 (2017).
126. Arnold AM, Holt BD, Daneshmandi L, Laurencin CT, Sydlik SA. Phosphate graphene as an intrinsically osteoinductive scaffold for stem cell-driven bone regeneration. Proc. Natl Acad. Sci. USA 116(11), 4855–4860 (2019).
127. Liu S, Mou S, Zhou C et al. Off-the-shelf biomimetic graphene oxide-collagen hybrid scaffolds wrapped with osteoinductive extracellular matrix for the repair of cranial defects in rats. ACS Appl. Mater. Interfaces 10(49), 42948–42958 (2018).
128. Uskokovic V, Desai TA. In vitro analysis of nanoparticulate hydroxyapatite/chitosan composites as potential drug delivery platforms for the sustained release of antibiotics in the treatment of osteomyelitis. J. Pharm. Sci.103(2), 567–579 (2014).
129. Ma S, Adayi A, Liu Z et al. Asymmetric collagen/chitosan membrane containing minocycline-loaded chitosan nanoparticles for guided bone regeneration. Sci. Rep. 6, 31822 (2016).
130. Mansour JM, Motavalli M, Dennis JE et al. Rapid detection of shear-induced damage in tissue-engineered cartilage using ultrasound. Tissue Eng. Part C Methods 24(8), 443–456 (2018).
131. Keller L, Schwinte P, Gomez-Barrena E, Arruebo M, Benkirane-Jessel N. Smart implants as a novel strategy to regenerate well-founded cartilage. Trends Biotechnol. 35(1), 8–11 (2017).
132. Ma YY, Jin KT, Wang SB et al. Molecular imaging of cancer with nanoparticle-based theranostic probes. Contrast Media Mol. Imaging 2017, 1026270 (2017).
133. Satpathy M, Wang L, Zielinski RJ et al. Targeted drug delivery and image-guided therapy of heterogeneous ovarian cancer using her2-targeted theranostic nanoparticles. Theranostics 9(3), 778–795 (2019).
134. Erol O, Sira MJP, Surgery R. New capillary bed formation with a surgically constructed arteriovenous fistula. Plast. Reconstr. Surg. 66(1), 109–115 (1980).
135. Yap KK, Yeoh GC, Morrison WA, Mitchell GM. The vascularised chamber as an in vivo bioreactor. Trends Biotech. 36(10), 1011–1024 (2018). •• Excellent review on the evolution and research surrounding the arteriovenous loop in vascular tissue engineering.
136. Schmidt VJ, Wietbrock JO, Leibig N et al. Collagen-elastin and collagen-glycosaminoglycan scaffolds promote distinct patterns of matrix maturation and axial vascularization in arteriovenous loop-based soft tissue flaps. Ann. Plast. Surg. 79(1), 92–100 (2017).
137. Morritt AN, Bortolotto SK, Dilley RJ et al. Cardiac tissue engineering in an in vivo vascularized chamber. Circulation 115(3), 353–360 (2007).
138. Weigand A, Beier JP, Hess A et al. Acceleration of vascularized bone tissue-engineered constructs in a large animal model combining intrinsic and extrinsic vascularization. Tissue Eng. Part A 21(9–10), 1680–1694 (2015).
139. Lu X, Zhu T, Chen C, Liu Y. Right or left: the role of nanoparticles in pulmonary diseases. Int. J. Mol. Sci. 15(10), 17577–17600 (2014).
140. Song Y, Tang S. Nanoexposure, unusual diseases, and new health and safety concerns. ScientificWorldJournal 11, 1821–1828 (2011).
141. Wolfram J, Zhu M, Yang Y et al. Safety of nanoparticles in medicine. Curr. Drug Targets 16(14), 1671–1681 (2015).
142. Bertrand N, Leroux JC. The journey of a drug-carrier in the body: an anatomo-physiological perspective. J. Control. Rel. 161(2), 152–163 (2012).
143. Szebeni J, Bedocs P, Csukas D, Rosivall L, Bunger R, Urbanics R. A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines. Adv. Drug Deliv. Rev. 64(15), 1706–1716 (2012).
144. Ozer K, Rojas-Pena A, Mendias CL, Bryner BS, Toomasian C, Bartlett RH. The effect of ex situ perfusion in a swine limb vascularized composite tissue allograft on survival up to 24 hours. J. Hand Surg. Am. 41(1), 3–12 (2016).
145. Werner NL, Alghanem F, Rakestraw SL et al. Ex situ perfusion of human limb allografts for 24 hours. Transplantation 101(3), e68–e74 (2017).
146. Lee SH, Sung JH. Organ-on-a-chip technology for reproducing multiorgan physiology. Adv. Healthc. Mater. 7(2), 1–17 (2018).
This article is excerpted from the Nanomedicine (Lond.) (2019) 14(20), 2679–2696 by Wound World.
