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Engineering Tissue-to-Tissue Interfaces and
the Formation of Complex Tissues

HELEN H. LU
Columbia University

Two significant challenges in the field of tissue engineering are the simultaneous formation of multiple types of tissues and the functional assembly of these tissues into complex organ systems (e.g., the skeletal, muscular, or circulatory systems). These challenges are particularly important for orthopedic regenerative medicine, as musculoskeletal motion requires synchronized interactions among many types of tissue and the seamless integration of bone with soft tissues such as tendons, ligaments, or cartilage. These tissue-to-tissue interfaces are ubiquitous in the body and exhibit a gradient of structural and mechanical properties that serve a number of functions, from mediating load transfer between two distinct types of tissue to sustaining the heterotypic cellular communications required for interface function and homeostasis (Benjamin et al. 1986; Lu and Jiang 2006; Woo et al. 1988). But these critical junctions are prone to injury (from trauma or even exercise and daily activity) and unfortunately do not regenerate after standard surgical repair, thus compromising graft stability and long-term clinical outcome (Friedman et al. 1985; Lu and Jiang 2006; Robertson et al. 1986). Consequently, there is a need for grafting systems that support biological fixation or integrative repair of soft tissues.

BACKGROUND

Through a combination of cells, growth factors, and/or biomaterials, the principles of tissue engineering (Langer and Vacanti 1993; Skalak 1988) have been readily applied to the formation of a variety of connective tissues such as bone, cartilage, ligament, and tendon both in vitro and in vivo. More recently, emphasis has shifted from tissue formation to tissue function (Butler et al. 2000), with a



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Engineering Tissue-to-Tissue Interfaces and the Formation of Complex Tissues Helen H. Lu Columbia University Two significant challenges in the field of tissue engineering are the simulta- neous formation of multiple types of tissues and the functional assembly of these tissues into complex organ systems (e.g., the skeletal, muscular, or circulatory systems). These challenges are particularly important for orthopedic regenerative medicine, as musculoskeletal motion requires synchronized interactions among many types of tissue and the seamless integration of bone with soft tissues such as tendons, ligaments, or cartilage. These tissue-to-tissue interfaces are ubiquitous in the body and exhibit a gradient of structural and mechanical properties that serve a number of functions, from mediating load transfer between two distinct types of tissue to sustaining the heterotypic cellular communications required for interface function and homeostasis (Benjamin et al. 1986; Lu and Jiang 2006; Woo et al. 1988). But these critical junctions are prone to injury (from trauma or even exercise and daily activity) and unfortunately do not regenerate after standard surgical repair, thus compromising graft stability and long-term clinical outcome (Friedman et al. 1985; Lu and Jiang 2006; Robertson et al. 1986). Consequently, there is a need for grafting systems that support biological fixation or integrative repair of soft tissues. BACKGROUND Through a combination of cells, growth factors, and/or biomaterials, the prin- ciples of tissue engineering (Langer and Vacanti 1993; Skalak 1988) have been readily applied to the formation of a variety of connective tissues such as bone, cartilage, ligament, and tendon both in vitro and in vivo. More recently, emphasis has shifted from tissue formation to tissue function (Butler et al. 2000), with a 117

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118 FRONTIERS OF ENGINEERING focus on imparting biomimetic functionality to orthopedic grafts and enabling their translation to the clinic. But clinical translation remains elusive as researchers seek to understand how to achieve biological fixation or functional integration of tissue-engineered orthopedic grafts—of bone, ligaments, or cartilage—with each other and/or with the host environment. The challenge is rooted in the complexity of the musculo- skeletal system and the structural intricacy of both hard and soft tissues. These tissues, each with a distinct cellular population, must operate in unison to facilitate physiologic function and maintain tissue homeostasis. It is thus not surprising that the transition between various tissue types is characterized by a high level of heterogeneous structural organization that is crucial for joint function. As shown in Figure 1, ligaments and tendons with direct insertions into bone exhibit a multitissue transition consisting of three distinct but continuous FIGURE 1  Common orthopedic tissue-to-tissue interfaces. Significant structural and com- positional homology exists in the orthopedic tissue-to-tissue interfaces of the tendon-bone (Benjamin and Ralphs 1998), muscle-tendon (Larkin et al. 2006), cartilage-bone (Hunziker et al. 2002), and ligament-bone junctions (Iwahashi et al. 2010). Regeneration of these complex junctions is essential for integrative soft tissue repair and treatment of massive, multitissue injuries. Tendon-to-bone interface: AC = articular cartilage, B = bone, CF = calcified fibrocartilage, CT = connective tissue, TM = tidemark, UF = uncalcified fibro- cartilage. Cartilage-to-bone interface: BM = bone marrow space, CC = calcified cartilage, R = radial zone, S = superficial zone, T = transitional zone.

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ENGINEERING TISSUE-TO-TISSUE INTERFACES 119 regions of ligament, fibrocartilage, and bone (Benjamin et al. 1986; Cooper and Misol 1970; Wang et al. 2006). The fibrocartilage interface is further divided into non­ alcified and calcified regions. In light of this complexity, effective tissue c engineering must incorporate strategic biomimicry or the prioritization of design parameters in order to regenerate the intricate tissue-to-tissue interface and ulti- mately enable seamless graft integration and functional repair. MECHANISMS OF INTERFACE REGENERATION The mechanisms underlying the formation, repair, and maintenance of tissue- to-tissue boundaries are not well understood. In particular, it is not known how distinct boundaries between different types of connective tissues are reestablished after injury. It is likely that mechanical loading (Killian et al. 2012) as well as chemical and biological factors play a role in this complex process. It has long been observed that when tendon is resutured to its original attach- ment site, cellular organization resembling that of the native insertion occurs in vivo (Fujioka et al. 1998). Investigators have also reported that, although healing after ligament reconstruction does not lead to the reestablishment of the native insertion, a layer of interface-like tissue forms in the bone tunnel (Blickenstaff et al. 1997; Grana et al. 1994; Rodeo et al. 1993). These observations suggest that when trauma or surgical intervention results in nonphysiologic exposure of normally segregated tissue types (e.g., bone or ligament), interactions between the resident cell populations (e.g., osteoblasts in bone, fibroblasts in tendon, stem cells/progenitor cells in both tissues) are critical for initiating and directing the repair response that leads to reestablishment of a fibrocartilage interface between soft tissue and bone. Specifically, it has been hypothesized that osteoblast-fibroblast interactions mediate interface regeneration through heterotypic cellular interactions that can lead to phenotypic changes or transdifferentiation of osteoblasts and/or fibroblasts (Lu and Jiang 2006). Moreover, these interactions may induce the differentia- tion of stem cells or resident progenitor cells into fibrochondrocytes and thereby promote the regeneration of the fibrocartilage interface. This hypothesis has been validated using coculture and triculture models of interface-relevant cell popula- tions (Jiang et al. 2005; Wang et al. 2007), models that offer simple and elegant methods to systematically investigate cell-cell interactions (Bhatia et al. 1999; Hammoudi et al. 2010). When ligament fibroblasts and osteoblasts were cocultured using a model permitting both physical contact and cellular interactions, it was observed that these controlled interactions altered cell growth and upregulated the expression of interface-related matrix markers. These cellular interactions have a down- stream effect, either inducing cell transdifferentiation or causing the recruitment and differentiation of progenitor or stem cells for fibrocartilage formation. When this hypothesis was tested in triculture, it was noted that under the influence of

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120 FRONTIERS OF ENGINEERING osteoblast-fibroblast interactions, stem cells from the bone marrow began to dif- ferentiate toward a chondrocyte-like phenotype, producing a matrix similar in composition to that of the interface. These intriguing findings suggest that heterotypic cellular communications play a regulatory role in the induction of interface-specific markers in progenitor or stem cells, and demonstrate the effects of these interactions in regulating the maintenance of soft tissue-to-bone junctions. The nature of the regulatory cyto- kines secreted and the mechanisms underlying these interactions are not known, but cell communication is likely to be significant for interface regeneration as well as homeostasis. Therefore the optimal interface scaffold must promote ­interactions between the relevant cell populations residing in each interface region. INTERFACE STRUCTURE-FUNCTION RELATIONSHIP AND DESIGN INSPIRATION From a structure-function perspective, the complex multitissue organiza- tion of the soft tissue-to-bone junction is optimized to sustain both tensile and compressive stresses experienced at the ligament-to-bone junction. Numerous characterization studies (Benjamin et al. 1986; Bullough and Jagannath 1983; Matyas et al. 1995; Moffat et al. 2008; Oegema and Thompson 1992; Ralphs et al. 1998; Spalazzi et al. 2004; Thomopoulos et al. 2003; Woo et al. 1988) have revealed remarkable organizational similarities among many tissue-to-tissue interfaces (Figure 1). They often consist of a multitissue, multicell transition and exhibit a controlled distribution of mineral content that, along with other structural parameters such as collagen fiber organization, results in a gradient of mechanical properties progressing from soft tissue to bone. Direct measurement of interface mechanical properties has been difficult due to the complexity and relatively small scale of the interface, generally ranging from 100 µm to 1 mm in length. Instead, knowledge of insertion material proper- ties has been largely derived from theoretical models. Moffat and colleagues (2008) recently performed the first experimental determination of the compressive mechanical properties of the anterior ­ ruciate c ligament (ACL)-bone interface in a neonatal bovine model. They evaluated the incremental displacement field of the fibrocartilage tissue under the applied uni- axial strain by coupling microcompression with optimized digital image correla- tion analysis of pre- and postloading images. Deformation decreased gradually from the fibrocartilage interface to bone, and these changes were accompanied by a gradual increase in compressive modulus. The interface also exhibited a region- dependent decrease in strain, and a significantly higher elastic modulus was found for the mineralized fibrocartilage compared to the nonmineralized region. These region-specific mechanical properties enable a gradual transition rather than a sud- den increase in tissue strain across the insertion, thereby minimizing the formation of stress concentrations and enabling load transfer from soft to hard tissues.

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ENGINEERING TISSUE-TO-TISSUE INTERFACES 121 Given the structure-function dependence inherent in the biological system, these regional changes in mechanical properties are likely correlated to matrix organization and composition across the interface. Partition of the fibrocartilage interface into nonmineralized and mineralized regions likely has a functional significance, as increases in matrix mineral content have been associated with higher mechanical properties in connective tissues. Evaluation of the insertion site using Fourier transform infrared imaging (Spalazzi et al. 2007) and X-ray analysis revealed an increase in calcium and phos- phorous content progressing from ligament to interface and then to bone. A narrow exponential transition in mineral content, instead of a linear gradient of mineral distribution, was detected progressing from the nonmineralized to the mineralized interface regions. Moreover, the increase in elastic modulus progressing from the mineralized to the nonmineralized fibrocartilage interface region was shown to be positively correlated (Moffat et al. 2008) with the presence of calcium phosphate. These observations have yielded invaluable clues for the design of biomimetic scaffolds for engineering tissue-to-tissue interface. Specifically, a stratified or multiphased scaffold will be essential for recapturing the multitissue organiza- tion observed at the soft tissue-to-bone interface. To minimize the formation of stress concentrations, the scaffold should exhibit phase-specific structural and mechanical properties, with a gradual increase in the latter across the scaffold phases. Spatial control of mineral distribution on a stratified scaffold can impart controlled mechanical heterogeneity similar to that of the native interface. Com- pared to a homogeneous structure, a scaffold with predesigned, tissue-specific matrix inhomogeneity can better sustain and transmit the distribution of complex loads inherent at the multitissue interface. It is important to bear in mind that the phases of a stratified scaffold must be interconnected and preintegrated with each other, to ensure the formation of compositionally distinct yet structurally contiguous multitissue regions. Further- more, interactions between interface-relevant cells serve important functions in the formation, maintenance, and repair of interfacial tissue. Therefore, precise control over the spatial distribution of these cell populations is also critical for multitissue formation and interface regeneration. Consideration of these ­biomimetic ­parameters should guide and optimize the design of stratified scaffolds for promoting the formation and maintenance of controlled matrix heterogeneity and interface regeneration. BIOINSPIRED SCAFFOLD DESIGN FOR INTERFACE TISSUE ENGINEERING Inspired by the native ACL-to-bone interface, Spalazzi and colleagues (2006, 2008) pioneered the design of a triphasic scaffold (Figure 2C) for the regenera- tion of this challenging interface. The scaffold’s three continuous phases are each engineered for a specific tissue region of the interface: Phase A is a polymer fiber

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122 FIGURE 2  Bioinspired stratified scaffold design for interface tissue engineering and integrative soft tissue repair.

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ENGINEERING TISSUE-TO-TISSUE INTERFACES 123 mesh for fibroblast culture and soft tissue formation, Phase B consists of polymer microspheres and is designed for fibrochondrocyte culture, and Phase C is com- posed of sintered polymer-ceramic composite microspheres for bone formation (Lu et al. 2003). The innovative design is in essence a single scaffold system with three compositionally distinct yet structurally continuous phases, all designed to support the formation of multitissue regions across the ligament-bone junction. To form the ligament, interface, and bone regions, fibroblasts, chondrocytes, and osteoblasts were seeded onto Phases A, B, and C, respectively. Interactions between these cell types on the stratified scaffold were evaluated both in vitro (Spalazzi et al. 2008) and in vivo (Spalazzi et al. 2006). Extensive tissue infil- tration and abundant matrix deposition were observed, with tissue continuity maintained across scaffold phases. Interestingly, matrix production compensated for the decrease in mechanical properties that accompanied scaffold degradation, and three continuous regions of ligament, interface, and bone-like matrix were formed in vivo (Figure 2E). In addition to stratified scaffolds, there is tremendous interest in designing scaffolds with a gradient of properties—that is, with a relatively gradual and continuous transition in either composition or structural organization, resulting in a linear gradient in mechanical properties (Harris et al. 2006; Seidi et al. 2011; Singh et al. 2008). These novel scaffolds with either a compositional (Erisken et al. 2008; Li et al. 2009) or chemical factor (Phillips et al. 2008; Singh et al. 2010) gradient offer direct regional control and allow for scaffold heterogeneity that mimics the complex native interface. They may thus address the need to recapitulate the complex transition of mechanical and chemical properties that are characteristic of tissue-to-tissue junctions. Design challenges in engineering biomimetic gradients revolve around scale—how best to recapitulate the micro- to nanoscale gradients that have been reported at the tissue-to-tissue interface. The stratified scaffold approach may represent a simpler strategy, whereby a gradation of key compositional and func- tional properties is preestablished by focusing on forming specific tissue regions of interest and preintegrating them through stratified design. In any case, it is necessary to adopt strategic biomimicry in functional interface scaffold design and to prioritize design parameters for interface regeneration based on the type of interface to be regenerated, the type and severity of injury, and the patient’s age and overall health. In addition to scaffold design, it is expected that cellular contributions will play a pivotal role in mediating the regeneration and homeostasis of the grada- tion of compositional and mechanical properties at the interface. For example, Ma and colleagues (2009) used cell self-assembly to form bone-ligament-bone constructs by culturing engineered bone segments to ligament monolayers. Paxton and colleagues (2009) also reported promising results when evaluating the use of a polymer ceramic composite and RGD peptide to engineer functional ligament- to-bone attachments.

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124 FRONTIERS OF ENGINEERING SUMMARY AND FUTURE DIRECTIONS The biomimetic interface tissue engineering approach described in this paper is rooted in an in-depth understanding of the inherent structure-function relation- ship at the tissue-to-tissue interface. The studies discussed indicate that control- ling cellular response via coculture, triculture, or growth factor distribution on multiphased scaffolds is a critical emerging strategy to enable the development of local gradients on a physiologically relevant scale. Many soft tissues connect to bone through a multitissue interface populated by multiple cell types that minimize the formation of stress concentrations while enabling load transfer between soft and hard tissues. In the event of injury or other disruption, reestablishment of tissue-to-tissue interfaces is critical for the formation of multitissue systems and the promotion of integrative tissue repair. Investigations into the mechanism of interface regeneration have revealed the role of mechanical loading as well as heterotypic cellular interactions in directing the formation, repair, and maintenance of the tissue-to-tissue interface. Moreover, functional and integrative repair may be achieved by coupling both cell- and s ­ caffold-based approaches. The vast potential of stratified scaffold systems is evi- dent because (1) they are designed to support multitissue regeneration by mediating heterotypic cellular interactions and (2) they can be further refined by incorporating well-controlled compositional and growth factor gradients as well as the use of bio- chemical and biomechanical stimulation to encourage tissue growth and maturation. Interface tissue engineering will be instrumental for the ex vivo development and in vivo regeneration of integrated musculoskeletal tissue systems with bio- mimetic functionality. Yet there remain a number of challenges in this exciting area. These include the need for a better understanding of the structure-function relationship at the native tissue-to-tissue interface and of the mechanisms that gov- ern interface development and regeneration. Furthermore, the in vivo host envi- ronment and the precise effects of biological, chemical, and physical stimulation on interface regeneration must be thoroughly evaluated to enable the formation and homeostasis of the new interface. Physiologically relevant in vivo models are needed to determine the clinical potential of designed scaffolds. The successful regeneration of tissue-to-tissue interfaces through a bio­ inspired approach may promote integrative and functional tissue repair and enable the clinical translation of tissue engineering technologies from bench to bedside. Moreover, by bridging distinct types of tissue, interface tissue engineering will be instrumental for the development of integrated musculoskeletal organ systems with biomimetic complexity and functionality. REFERENCES Benjamin M, Ralphs JR. 1998. Fibrocartilage in tendons and ligaments: An adaptation to compressive load. Journal of Anatomy 193(Pt 4):481–494.

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