571308 review-article2015

JHS0010.1177/1753193415571308Journal of Hand Surgery (European Volume)Kloczko et al.


Review Article

Scaffolds for hand tissue engineering: the importance of surface topography E. Kloczko1, D. Nikkhah2 and L. Yildirimer3,4

The Journal of Hand Surgery (European Volume) XXE(X) 1­–13 © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1753193415571308 jhs.sagepub.com

Abstract Tissue engineering is believed to have great potential for the reconstruction of the hand after trauma, congenital absence and tumours. Due to the presence of multiple distinct tissue types, which together function in a precisely orchestrated fashion, the hand counts among the most complex structures to regenerate. As yet the achievements have been limited. More recently, the focus has shifted towards scaffolds, which provide a three-dimensional framework to mimic the natural extracellular environment for specific cell types. In particular their surface structures (or topographies) have become a key research focus to enhance tissuespecific cell attachment and growth into fully functioning units. This article reviews the current understanding in hand tissue engineering before focusing on the potential for scaffold topographical features on micro- and nanometre scales to achieve better functional regeneration of individual and composite tissues. Keywords Hand tissue engineering, biomaterial scaffolds, surface micro-/nano-structures, stem cells, clinical translation Date received: 24th June 2014; revised: 8th January 2015; accepted: 14th January 2015

Introduction The hand distinguishes humans from primates, being more muscular and mobile and equipped with a fully opposable thumb combined with shorter and straighter fingers (Young, 2003). Hand surgery has made many advances in reconstruction, but like many other specialties, continues to face tissue shortages for reconstruction after trauma, tumour resection and congenital absence (Chong and Chang, 2006). Current techniques include the use of arthroplasties, joint fusion and flap transfers from auto- or allogeneic sources, etc. However, they have disadvantages including implant infection, extrusion and dislocation, as well as flap failure and donor site morbidity. Furthermore there are high failure rates following some arthroplasties and limited long-term studies of patient outcomes (Giddins, 2012). Upper limb vascularized composite allotransplantation has already been performed in many units worldwide. However, the risk of immunosuppression to healthy individuals and the length of time the transplant will survive have yet to be quantified (Brügger, 2014; Kay and Wilks, 2013). It is hoped that tissue engineering can improve current hand reconstructive techniques by eliminating the negative aspects of allotransplantation while achieving similar or superior

function. Novel strategies, involving the use of biocompatible tissue scaffolds, cellular components and growth factors aim to restore, maintain or improve tissue function (Figure 1). While the latter two remain a mainstay of current research efforts, as evidenced by the focus of recent reviews (Janicki and Schmidmaier, 2011; Lundborg, 2004), this article will highlight a relatively underrepresented area in hand tissue engineering – the field of biomaterial surface topography. This field is concerned with understanding and so manipulating cell behaviour through differences in


School of Life and Medical Sciences, University College London, London, UK 2The Queen Victoria Hospital, East Grinstead, UK 3Centre for Nanotechnology & Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, UK 4Department of Plastic and Reconstructive Surgery, Royal Free Hospital Hampstead NHS Trust, London, UK Corresponding author: Lara Yildirimer, Centre for Nanotechnology & Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, UK. Email: [email protected]

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The Journal of Hand Surgery (Eur)

Figure 1.  Concept of tissue engineering.

micro- and nanoscopic surface features on scaffolds. The three-dimensional effect of biomaterial scaffolds has only recently been acknowledged to provide more than a passive physical structure for cells attachment. It is now understood to be able to direct cell fates and proliferation rates by influencing intracellular molecular cascades and therefore gene expression (Klapperich and Bertozzi, 2004; Zhou et al., 2013). This ability, albeit not fully understood, is hypothesized to be of fundamental importance in both structural as well as functional tissue regeneration. By altering the scaffold surface structure, the ability for cells and proteins to adhere or resist attachment can be fine-tuned. This may help solve commonly encountered problems in hand tissue engineering, such as post-transplant adhesions. One of the main difficulties of scaffold-based attempts at tissue regeneration is that as tissue architecture becomes more complex and hierarchical, scaffold design must match such complexity (Webber et al., 2014). Hence, the scaffold shape and texture might have to be diversified throughout the structure to provide mechanical cues for development of different components of replaced tissue. Before discussing novel approaches to scaffold surface texturing, we will review current tissue engineering strategies in hand surgery.

Bone tissue engineering Bones can self-heal as shown in fracture healing (Egermann et al., 2006; Nandi et al., 2010). Larger or complex defects may fail to heal due to a lack of blood

supply, infection or systemic disease (Bansal et al., 2009; Bigham et al., 2008; Hegde et al., 2013). Bone, usually autologous, is among the most commonly transplanted tissues (Elsalanty and Genecov, 2009; Nandi et al., 2010). There can be donor site complications such as pain and injury to adjacent structures (Murata et al., 2002). Vascularized autologous bone grafting using a corticoperiosteal flap has been described for scaphoid non-union, but can be technically challenging (Del Pinal et al., 2007). Allo- and xenografts are associated with risks, particularly graft rejection and disease transmission (Ehrler and Vaccaro, 2000; Yazar, 2010). Ideally, an off-the-shelf vascularized bone graft would solve such challenges. Options using non-biological synthetic scaffolds have been investigated (see Table 1). Maintaining adequate vascularization throughout the entire construct is often the biggest challenge. A lack of a vascular network results in inadequate oxygenation and nutrient provision, as well as a build-up of waste products. Cellular and growth factor (GF) supplementation of scaffolds or plates used for conventional surgical fixation have gained popularity due to their ability to accelerate new vessel and tissue formation (Govender et al., 2002). Increasing angiogenesis using vascular endothelial growth factor (VEGF), a pro-angiogenic factor, has been shown to improve bone formation (Peng et al., 2005). So far, bone tissue engineering has been successfully employed in craniofacial and limb reconstruction procedures giving promise of a role in hand surgery (Hibi et al., 2006; Montesani et al., 2011; Yamada et al., 2008).

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Kloczko et al. Table 1.  Examples of biomaterials used in bone tissue engineering. Scaffold material and fabrication



Clinical significance

HA (65%) and β-TCP (35%) – cylindrical structures with 8 mm internal diameter. Bruder et al. (1998)

Cylinders incubated in medium filled with caninederived MSCs for hours and implantation into 21 mm long femoral diaphyseal defect in skeletally matured hounds.

Highlights the potential to reduce donor-site morbidity by harvesting autologous stem cells from the patient’s iliac crest as an alternative to autologous bone-grafting.

Gelatin (Gelfoam®) – commercially available. Peng et al. (2005)

MDCs transduced to express VEGF, BMP-2 or sFft1 (VEGF antagonist), seeded onto scaffolds and implanted into 6 mm murine calvarial defects.

Significant bone formation and histological evidence of woven and lamellar reestablishment observed in scaffolds loaded with cells. No bone formation in untreated animals. Addition of exogenous VEGF enhanced BMP-2 induced bone formation and angiogenesis synergistically.

PRP + human thrombin – three-way stopcock connected to two syringes; one containing air, CaCl2 and thrombin, the other PRP and human BMSCs. Mixed for 5 s. Yamada et al. (2008)

Injectable bone was used to augment maxillary sinus floor and simultaneously place dental implants in severe posterior alveolar ridge atrophy.

PRP + human thrombin – three-way stopcock connected to two syringes; one containing air, CaCl2 and thrombin the other PRP and human MSCs. Mixed for 5 s. Hibi et al. (2006)

Cells differentiated in vitro in osteogenic medium and injected into distracted tissue into a space encapsulated by a titanium mesh post mandibular resection.

Osseointegration between implants and regenerated bones after 3.5 years. The average healing period was 6.4 months with no adverse effects and bone absorption. The mean increase in the height of mineralized tissue was 8.8 mm after 2 years post-surgery. Three months after distraction, newly formed bone in the distraction gap appeared to have a relatively even density.

A better understanding of the interactions between different growth factors contributes to development of more effective therapeutic strategies to improve bone healing. Minimally invasive injectable tissue-engineered bone composed of BMSC and PRP generated donor derived osteoblasts improving masticatory function.

Conventionally used vascularized fibular flaps for reconstruction of the mandible requires multiple osteotomies that interrupt the medullary vessel. Autologous injectable bone is an alternative ensuring better vascular supply.

β-TCP: β-tricalcium phosphate: BMP-2: bone morphogenic protein-2; BMSCs: bone marrow stem cells; HA: hydroxyapatite; MDCs: muscle derived cells; MSC: mesenchymal stem cells; PRP: platelet-rich plasma; sFft1: soluble fms-like tyrosine kinase-1; VEGF: vascular endothelial growth factor.

Cartilage tissue engineering Tissue engineering of cartilaginous tissues, specifically for hand and digit reconstruction, has made little progress in the past 15 years. Isogai et al. (1999) demonstrated the formation of mature articular cartilage as well as subchondral bone using a scaffold incorporated into a structure similar to human phalanges and joints. Bovine periosteum was wrapped around a polyglycolic/polylactic acid (PGA/PLA) scaffold. Separate PGA sheets were then impregnated with chondrocytes and tenocytes and a composite tissue structure was created in vitro by assembling the scaffolds and sheets into models resembling the different bones of a phalanx. Similar studies have confirmed this approach (Landis et al., 2009; Sedrakyan et al., 2006). Such hybrid approaches, where natural materials (e.g. hyaluronic acid, elastin and alginate hydrogels) are incorporated

into synthetic polymer-based scaffolding materials such as polycaprolactone (PCL), have gained popularity as they provide cues for cell growth (natural component) and the physical strength (synthetic component) required for cartilage tissue engineering. The PCL component increases the hybrid scaffold’s stiffness close to that of normal bone (Mintz and Cooper, 2014). The natural component, on the other hand, promotes a rounded chondrocyte morphology resembling that found in vivo. However, the collagen expression was no different to PCL-only scaffolds, indicating that parameters above and beyond material types are required to influence cell behaviour. There have also been successful attempts to enhance cartilage engineering by using bioreactors; these are devices used to recreate a physiological environment in vitro or in vivo in order to promote tissue growth and differentiation. In particular, it was found that periodically (every three days)

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The Journal of Hand Surgery (Eur)

reversing the flow of the medium within the bioreactor could significantly enhance cartilage tissue formation, which was likely due to improved cell access to GFs dispersed within the medium (Mahmoudifar and Doran, 2005). Despite initial promising results, the optimal scaffold and bioreactor combination remains elusive with little recent progress.

Tendon autografts, including local and distant and vascularized and non-vascularized tendon transfers, are performed commonly (Cavadas et al., 2014; Danoff et al., 2014; Kotkansalo et al., 2014; Lee et al., 2014). However, limited donor tendons and the potential for scarring and adhesions occur particularly when intrasynovial tendons are replaced by extrasynovial grafts (Majima et al., 2005; Zhang et al., 2009). The only intrasynovial tendon source outside of the hands is the flexor digitorum longus of the foot. Ozturk et al. (2008) successfully recreated a synovial membrane by impregnating a collagen type I matrix with rat synovial cells, which is also feasible in vivo as demonstrated in a rabbit flexor tendon model (Table 2) (Baymurat et al., 2014) . The main limitations of tendon tissue engineering include suboptimal mechanical properties of the neo-tendon in comparison with the autologous tendon and the difficulties in creating the multiple planes between the tendon and synovial sheath as well as the pulleys to allow for smooth gliding (Chen et al., 2012a). It has been showed that a scaffold allowing controlled release of transforming growth factor β3 (TGF-β3) can reduce tendon adhesion formation in vitro. This has been achieved by incorporating TGF-β3 microspheres into a three-dimensional chitosan scaffold in vitro (Jiang et al., 2014). Further investigations are required to elucidate the potential mechanisms of actions which can reverse or prevent adhesion formation.

their superior mechanical properties. However, foreign-body reactions and the impermeability to oxygen and nutrients drive the search for biodegradable alternatives, which may be enhanced further to attract or deliver bioactive agents such as Schwann cells (Biazar and Keshel, 2013; Tran et al., 2013). Due to lengthy culture times, the delivery of Schwann cells into acute nerve injury sites currently remains impractical (Schmitte et al., 2010; Zhang et al., 2002). Other cell sources, such as neural stem cells, once thought to be a potential alternative, led to tumours in rat models (Amado et al., 2010; Radtke et al., 2010). Mesenchymal stem cells derived from adult tissues appear to be promising for nerve tissue engineering due to a reduced risk of malignant transformation (Cho et al., 2010). When used in combination with a nerve conduit made from chitosan/poly(lactic co-glycolic)acid (PLGA) efficient nutrient diffusion and blood vessels formation was established (Hu et al., 2013). Chitosan, a linear polysaccharide derived from chitin (a structural component in crustaceans) is known for its anti-tumour and antibacterial properties. This renders it an attractive candidate for nerve tissue engineering (Wang et al., 2005). Interestingly, there are case reports of positive outcomes of chitosan/PGA composite scaffolds for digital or median nerve reconstruction in humans (Gu et al., 2012). The benefits of using degradable materials, such as PGA or chitosan, include relatively rapid scaffold hydrolysis within 90 days of implantation with end-results superior to nerve autografts when used in gaps of 3–8 mm (Weber et al., 2000). Additionally, biodegradable scaffolds are capable of delivering bioactive agents, such as fibroblast growth factor (FGF), glial growth factor (GGF) or neuron growth factor (NGF), which accelerate cellular proliferation and differentiation (Mohanna et al., 2005; Takagi et al., 2012; Yan et al., 2012). Table 3 outlines examples of nerve tissue engineering using synthetic or biological scaffold materials.

Nerve tissue engineering

Blood vessel tissue engineering

Nerve lesions are conventionally treated with end-toend neurorrhaphy (gap

Scaffolds for hand tissue engineering: the importance of surface topography.

Tissue engineering is believed to have great potential for the reconstruction of the hand after trauma, congenital absence and tumours. Due to the pre...
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