The successful metamorphosis of tissue-to-tissue interfaces by a bioinspired proceed might capacitate a interpretation of hankie engineering technologies from dais to bedside.
Two poignant hurdles in a margin of hankie engineering are a coexisting arrangement of mixed forms of tissues and a organic public of these tissues into formidable organ systems (e.g., a skeletal, muscular, or circulatory systems). These hurdles are quite vicious for orthopedic regenerative medicine, as musculoskeletal suit requires synchronized interactions among many forms of hankie and a seamless arrangement of bone with soothing tissues such as tendons, ligaments, or cartilage. These tissue-to-tissue interfaces are entire in a physique and vaunt a slope of constructional and automatic properties that offer a series of functions, from mediating bucket send between dual graphic forms of hankie to nutritious a heterotypic mobile communications compulsory for interface duty and homeostasis (Benjamin et al. 1986; Lu and Jiang 2006; Woo et al. 1988). But these vicious junctions are disposed to damage (from mishap or even practice and daily activity) and unfortunately do not renovate after customary surgical repair, so compromising swindle fortitude 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 soothing tissues.
Background
Through a mixed of cells, expansion factors, and/or biomaterials, a beliefs of hankie engineering (Langer and Vacanti 1993; Skalak 1988) have been straightforwardly practical to a arrangement of a accumulation of connection tissues such as bone, cartilage, ligament, and tendon both in vitro and in vivo. More recently, importance has shifted from hankie arrangement to hankie duty (Butler et al. 2000), with a concentration on imparting biomimetic functionality to orthopedic grafts and enabling their interpretation to a clinic.
But clinical interpretation stays fugitive as researchers find to know how to grasp biological emplacement or organic arrangement of tissue-engineered orthopedic grafts—of bone, ligaments, or cartilage—with any other and/or with a horde environment. The plea is secure in a complexity of a musculoskeletal complement and a constructional meandering of both tough and soothing tissues. These tissues, any with a graphic mobile population, contingency work in unanimity to foster physiologic duty and say hankie homeostasis. It is so not startling that a transition between several hankie forms is characterized by a high turn of extrinsic constructional classification that is essential for corner function.
Figure 1
As shown in Figure 1, ligaments and tendons with proceed insertions into bone vaunt a multitissue transition consisting of 3 graphic though continual regions of ligament, fibrocartilage, and bone (Benjamin et al. 1986; Cooper and Misol 1970; Wang et al. 2006). The fibrocartilage interface is offer divided into noncalcified and calcified regions. In light of this complexity, effective hankie engineering contingency incorporate strategic biomimicry or a prioritization of pattern parameters in sequence to renovate a perplexing tissue-to-tissue interface and eventually capacitate seamless swindle arrangement and organic repair.
Mechanisms of Interface Regeneration
The mechanisms underlying a formation, repair, and upkeep of tissue-to-tissue bounds are not good understood. In particular, it is not famous how graphic bounds between opposite forms of connection tissues are reestablished after injury. It is approaching that automatic loading (Killian et al. 2012) as good as chemical and biological factors play a purpose in this formidable process.
It has prolonged been celebrated that when tendon is resutured to a strange connection site, mobile classification imitative that of a internal insertion occurs in vivo (Fujioka et al. 1998). Investigators have also reported that, nonetheless recovering after vinculum reformation does not lead to a reestablishment of a internal insertion, a covering of interface-like hankie forms in a bone hovel (Blickenstaff et al. 1997; Grana et al. 1994; Rodeo et al. 1993). These observations advise that when mishap or surgical involvement formula in nonphysiologic bearing of routinely segregated hankie forms (e.g., bone or ligament), interactions between a proprietor dungeon populations (e.g., osteoblasts in bone, fibroblasts in tendon, branch cells/progenitor cells in both tissues) are vicious for initiating and directing a correct response that leads to reestablishment of a fibrocartilage interface between soothing hankie and bone.
Specifically, it has been hypothesized that osteoblast-fibroblast interactions intercede interface metamorphosis by heterotypic mobile interactions that can lead to phenotypic changes or transdifferentiation of osteoblasts and/or fibroblasts (Lu and Jiang 2006). Moreover, these interactions might satisfy a split of branch cells or proprietor progenitor cells into fibrochondrocytes and thereby foster a metamorphosis of a fibrocartilage interface. This supposition has been certified determining coculture and triculture models of interface-relevant dungeon populations (Jiang et al. 2005; Wang et al. 2007), models that offer elementary and superb methods to evenly examine cell-cell interactions (Bhatia et al. 1999; Hammoudi et al. 2010).
When vinculum fibroblasts and osteoblasts were cocultured determining a indication needing both earthy hit and mobile interactions, it was celebrated that these tranquil interactions altered dungeon expansion and upregulated a countenance of interface-related pattern markers. These mobile interactions have a downstream effect, possibly inducing dungeon transdifferentiation or causing a recruitment and split of progenitor or branch cells for fibrocartilage formation. When this supposition was tested in triculture, it was conspicuous that underneath a change of osteoblast-fibroblast interactions, branch cells from a bone pith began to compute toward a chondrocyte-like phenotype, producing a pattern identical in combination to that of a interface.
These intriguing commentary advise that heterotypic mobile communications play a regulatory purpose in a initiation of interface-specific markers in progenitor or branch cells, and denote a effects of these interactions in determining a upkeep of soothing tissue-to-bone junctions. The inlet of a regulatory cytokines secreted and a mechanisms underlying these interactions are not known, though dungeon communication is approaching to be poignant for interface metamorphosis as good as homeostasis. Therefore a optimal interface skeleton contingency foster interactions between a applicable dungeon populations staying in any interface region.
Interface Structure-Function Relationship and Design Inspiration
From a structure-function perspective, a formidable multitissue classification of a soothing tissue-to-bone connection is optimized to means both tensile and compressive stresses gifted during a 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 suggested conspicuous organizational similarities among many tissue-to-tissue interfaces (Figure 1). They mostly embody of a multitissue, multicell transition and vaunt a tranquil placement of vegetable calm that, along with other constructional parameters such as collagen fiber organization, formula in a slope of automatic properties surpassing from soothing hankie to bone.
Direct dimensions of interface automatic properties has been formidable due to a complexity and comparatively tiny scale of a interface, generally trimming from 100 µm to 1 mm in length. Instead, believe of insertion element properties has been mostly subsequent from fanciful models.
Moffat and colleagues (2008) recently achieved a initial initial integrity of a compressive automatic properties of a maiden cruciate vinculum (ACL)-bone interface in a neonatal cow model. They evaluated a incremental banishment margin of a fibrocartilage hankie underneath a practical uniaxial aria by coupling microcompression with optimized digital picture association research of pre- and postloading images. Deformation decreased gradually from a fibrocartilage interface to bone, and these changes were accompanied by a light boost in compressive modulus. The interface also exhibited a region-dependent diminution in strain, and a significantly aloft effervescent modulus was found for a mineralized fibrocartilage compared to a nonmineralized region. These region-specific automatic properties capacitate a light transition rather than a remarkable boost in hankie aria opposite a insertion, thereby minimizing a arrangement of highlight concentrations and enabling bucket send from soothing to tough tissues.
Given a structure-function coherence fundamental in a biological system, these informal changes in automatic properties are approaching correlated to pattern classification and combination opposite a interface. Partition of a fibrocartilage interface into nonmineralized and mineralized regions approaching has a organic significance, as increases in pattern vegetable calm have been compared with aloft automatic properties in connection tissues.
Evaluation of a insertion site determining Fourier renovate infrared imaging (Spalazzi et al. 2007) and X-ray research suggested an boost in calcium and phosphorous calm surpassing from vinculum to interface and afterwards to bone. A slight exponential transition in vegetable content, instead of a linear slope of vegetable distribution, was rescued surpassing from a nonmineralized to a mineralized interface regions. Moreover, a boost in effervescent modulus surpassing from a mineralized to a nonmineralized fibrocartilage interface segment was shown to be definitely correlated (Moffat et al. 2008) with a participation of calcium phosphate.
These observations have yielded useful clues for a pattern of biomimetic scaffolds for engineering tissue-to-tissue interface. Specifically, a stratified or multiphased skeleton will be essential for recapturing a multitissue classification celebrated during a soothing tissue-to-bone interface. To minimize a arrangement of highlight concentrations, a skeleton should vaunt phase-specific constructional and automatic properties, with a light boost in a latter opposite a skeleton phases. Spatial control of vegetable placement on a stratified skeleton can explain tranquil automatic heterogeneity identical to that of a internal interface. Compared to a comparable structure, a skeleton with predesigned, tissue-specific pattern inhomogeneity can softened means and broadcast a placement of formidable loads fundamental during a multitissue interface.
It is vicious to bear in mind that a phases of a stratified skeleton contingency be companion and preintegrated with any other, to safeguard a arrangement of compositionally distinct nonetheless structurally contiguous multitissue regions. Furthermore, interactions between interface-relevant cells offer vicious functions in a formation, maintenance, and correct of interfacial tissue. Therefore, accurate control over a spatial placement of these dungeon populations is also vicious for multitissue arrangement and interface regeneration. Consideration of these biomimetic parameters should beam and optimize a pattern of stratified scaffolds for compelling a arrangement and upkeep of tranquil pattern heterogeneity and interface regeneration.
Figure 2
Bioinspired Scaffold Design for Interface Tissue Engineering
Inspired by a internal ACL-to-bone interface, Spalazzi and colleagues (2006, 2008) pioneered a pattern of a triphasic skeleton (Figure 2C) for a metamorphosis of this severe interface. The scaffold’s 3 continual phases are any engineered for a specific hankie segment of a interface: Phase A is a polymer fiber filigree for fibroblast enlightenment and soothing hankie formation, Phase B consists of polymer microspheres and is designed for fibrochondrocyte culture, and Phase C is stoical of sintered polymer-ceramic combination microspheres for bone arrangement (Lu et al. 2003). The innovative pattern is in hint a singular skeleton complement with 3 compositionally graphic nonetheless structurally continual phases, all designed to support a arrangement of multitissue regions opposite a ligament-bone junction.
To form a ligament, interface, and bone regions, fibroblasts, chondrocytes, and osteoblasts were seeded onto Phases A, B, and C, respectively. Interactions between these dungeon forms on a stratified skeleton were evaluated both in vitro (Spalazzi et al. 2008) and in vivo (Spalazzi et al. 2006). Extensive hankie infiltration and abounding pattern deposition were observed, with hankie smoothness confirmed opposite skeleton phases. Interestingly, pattern prolongation compensated for a diminution in automatic properties that accompanied skeleton degradation, and 3 continual regions of ligament, interface, and bone-like pattern were shaped in vivo (Figure 2E).
In serve to stratified scaffolds, there is extensive seductiveness in conceptualizing scaffolds with a slope of properties—that is, with a comparatively light and continual transition in possibly combination or constructional organization, ensuing in a linear slope in automatic properties (Chatterjee et al. 2011; Harris et al. 2006; Seidi et al. 2011; Singh et al. 2008). These novel scaffolds with possibly a compositional (Erisken et al. 2008; Li et al. 2009) or chemical cause (Phillips et al. 2008; Singh et al. 2010) slope offer proceed informal control and concede for skeleton heterogeneity that mimics a formidable internal interface. They might so residence a need to reproduce a formidable transition of automatic and chemical properties that are evil of tissue-to-tissue junctions.
Design hurdles in engineering biomimetic gradients revolve around scale—how best to reproduce a micro- to nanoscale gradients that have been reported during a tissue-to-tissue interface. The stratified skeleton proceed might paint a easier strategy, whereby a gradation of pivotal compositional and organic properties is preestablished by focusing on combining specific hankie regions of seductiveness and preintegrating them by stratified design. In any case, it is required to adopt vital biomimicry in organic interface skeleton pattern and to prioritize pattern parameters for interface metamorphosis formed on a form of interface to be regenerated, a form and astringency of injury, and a patient’s age and altogether health.
In serve to skeleton design, it is approaching that mobile contributions will play a pivotal purpose in mediating a metamorphosis and homeostasis of a gamut of compositional and automatic properties during a interface. For example, Ma and colleagues (2009) used dungeon self-assembly to form bone-ligament-bone constructs by culturing engineered bone segments to vinculum monolayers. Paxton and colleagues (2009) also reported earnest formula when evaluating a use of a polymer ceramic combination and RGD peptide to engineer organic ligament-to-bone attachments.
Summary and Future Directions
The biomimetic interface hankie engineering proceed described in this paper is secure in an in-depth bargain of a fundamental structure-function attribute during a tissue-to-tissue interface. The studies discussed prove that determining mobile response around coculture, triculture, or expansion cause placement on multiphased scaffolds is a vicious rising plan to capacitate a expansion of internal gradients on a physiologically applicable scale.
Many soothing tissues bond to bone by a multitissue interface populated by mixed dungeon forms that minimize a arrangement of highlight concentrations while enabling bucket send between soothing and tough tissues. In a eventuality of damage or other disruption, reestablishment of tissue-to-tissue interfaces is vicious for a arrangement of multitissue systems and a graduation of unifying hankie repair.
Investigations into a resource of interface metamorphosis have suggested a purpose of automatic loading as good as heterotypic mobile interactions in directing a formation, repair, and upkeep of a tissue-to-tissue interface. Moreover, organic and unifying correct might be achieved by coupling both cell- and scaffold-based approaches. The immeasurable intensity of stratified skeleton systems is clear as (1) they are designed to support multitissue metamorphosis by mediating heterotypic mobile interactions and (2) they can be offer polished by incorporating well-controlled compositional and expansion cause gradients as good as a use of biochemical and biomechanical kick to inspire hankie expansion and maturation.
Interface hankie engineering will be instrumental for a ex vivo expansion and in vivo metamorphosis of integrated musculoskeletal hankie systems with biomimetic functionality. Yet there sojourn a series of hurdles in this sparkling area. These embody a need for a softened bargain of a structure-function attribute during a internal tissue-to-tissue interface and of a mechanisms that oversee interface expansion and regeneration. Furthermore, a in vivo horde sourroundings and a accurate effects of biological, chemical, and earthy kick on interface metamorphosis contingency be entirely evaluated to capacitate a arrangement and homeostasis of a new interface. Physiologically applicable in vivo models are indispensable to establish a clinical intensity of designed scaffolds.
The successful metamorphosis of tissue-to-tissue interfaces by a bioinspired proceed might foster unifying and organic hankie correct and capacitate a clinical interpretation of hankie engineering technologies from dais to bedside. Moreover, by bridging graphic forms of tissue, interface hankie engineering will be instrumental for a expansion of integrated musculoskeletal organ systems with biomimetic complexity and functionality.
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