Keywords

1 Introduction

Musculoskeletal conditions affect millions of people and are the second leading cause of disability worldwide [1]. Through orthopedic care , patients can find pain relief, increased mobility, and improved quality of life, thus bettering the lives of individuals and improving society as a whole. Many orthopedic procedures require implants, and advances over the past half-century have allowed for the development of biomaterials with both enhanced mechanical and biological function [2]. Despite these improvements, many implants do not last forever: up to 15% of total joint implants require operative revision within 15 years of initial surgery [3, 4]. With over one million Americans undergoing total joint replacement annually, there is a need to improve the biological function and longevity of orthopedic biomaterials [5].

It is well known that inflammation is induced by implants and their resulting wear particles . On the other hand, early, transient inflammation is essential for proper bone formation and osseointegration of the implant [6]. This process is mediated through prostaglandins and macrophage-related inflammation, mimicking the natural fracture healing response beginning with acute inflammation and resolving into repair and regeneration of peri-implant tissues [7, 8]. However, if inflammation continues, the body may mount a foreign body chronic inflammatory reaction, leading to enhanced and persisting inflammation, bone resorption, osteolysis, and ultimately implant failure [3]. Wear particles produced from the bearing surface, modular connections, and motion at the interface of the implant and bone can activate the NALP inflammasome, the NF-κB pathway, and toll-like receptors (TLR)-2 and TLR-4 depending on the material, size of the particles, and surface topology, which are reviewed thoroughly by Cobelli et al., Gibon et al., and Lin et al. [4, 9, 10].

Chronic inflammation can arise from aberrant activity of the immune system to clear wear particles . If wear debris are too large for macrophages to remove, macrophages fuse to form multinucleated foreign body giant cells (FBGCs) [11]. Normally, these FBGCs are able to degrade or sequester wear particles, allowing for short-lived inflammation, and eventual resolution and repair; however, if the immune system is overwhelmed by excessive particles of appropriate size, inflammation persists [10]. This inflammation in conjunction with continued micromotion propagates wear debris formation, macrophage and T cell infiltration, and eventual osteolysis [10, 12]. As such, chronic inflammation is a vicious cycle of persistent inflammation, implant wear, and bone loss.

The longevity of an orthopedic implant is dependent upon the implant material, operative procedure, and patient-related factors [3]. Precise modulation of inflammation post-operatively has the potential to increase the lifespan of orthopedic implants. By integrating our understanding of the cellular and molecular mechanisms underlying prolonged inflammation, it is possible to develop optimized biomaterials that not only mitigate chronic inflammation, but also enhance osseointegration, vascularization, mechanical strength, and long-term healing.

2 Inflammation and Immunomodulating Strategy

2.1 Innate Immune Response and Macrophages

Cells of the innate immune system, particularly macrophages , are the main inflammatory mediators that drive successful implant integration or rejection [13, 14]. Macrophages also play a crucial role in tissue maintenance and regulation of inflammation [15, 16]. All tissues contain a specific set of macrophages known as tissue resident macrophages that remove damaged, senescent, and infected cells to maintain tissue homeostasis. These tissue resident macrophages originate from circulating, myeloid-derived, monocytes or, in some cases, are distributed among tissues during embryonic development and are maintained by local pools of precursor cells [17]. Macrophages are specialized to effectively phagocytize and remove cellular debris, microbes, and foreign substances identified as potentially dangerous or pathogenic. These foreign agents are recognized by various families of pattern recognition receptors (PRRs) that are expressed on the cell surface, endosomes, and cytoplasm of macrophages [18, 19]. Activation of PRRs initiates intracellular downstream signaling pathways that activate phagocytosis and can lead to the secretion of various cytokines and chemokines. The degree of this innate immune response depends on the nature and amount of the activating stimuli: phagocytosis of apoptotic cells induces an anti-inflammatory response to maintain tissue homeostasis and immune tolerance, while recognition of necrotic cells, damaged extracellular matrix, or pathogens initiates a pro-inflammatory response [19, 20]. Secreted inflammatory mediators then stimulate further cytokine secretion from other resident cells and recruit more immune cells to the site of inflammation. During acute or chronic inflammation, a large number of bone marrow-derived monocytes are recruited from the circulation to the inflamed tissues and undergo differentiation to inflammatory or tissue regenerative macrophages as guided by the local microenvironment [21].

Following the recognition of threatening agents, macrophages engulf these agents to restrict any deleterious effects on adjacent tissues. This phagocytosis process triggers enzymatic degradation of the engulfed material inside macrophages in some cases and, in the case of foreign biological structures, leads to antigen presentation to activate the adaptive immune response. As regulated by macrophages , the immune system thus attempts to efficiently dispose of the harmful substance, kill the microbes encountered, and prevent further tissue injury. As an inflammatory reaction proceeds and the danger becomes resolved, macrophages begin to promote tissue healing and regeneration by secreting extra-cellular matrix precursors, a range of growth factors such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), and anti-inflammatory cytokines [22]. The cytokine signaling in the local microenvironment thus coordinates the development of an immune response and macrophage function [23].

2.2 Macrophage Polarization

Macrophages are able to undergo functional changes as instructed by the surrounding cytokine milieu in tissues [16]. These phagocytes assume a distinct phenotype with divergent inflammatory, fibrotic, and regenerative properties necessary for different phases of inflammation and tissue regeneration. Initially, macrophages become activated to a pro-inflammatory phenotype following the recognition of a stimulating agent by PRRs. The specific factors promoting this classical macrophage activation, known as M1 polarization , is comprised of endogenous danger signals released from necrotic cells and pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), released from various invading micro-organisms. Activators with a similar effect also include cytokines, especially, interferon gamma (IFN-γ), granulocyte-monocyte colony stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-α) [24]. Macrophages with a pro-inflammatory phenotype are essential for the early phase of repair, but prolonged inflammation by these M1 macrophages exacerbate tissue injury by actively phagocytizing potential pathogens, killing intracellular microbes by producing oxygen and nitrogen radicals, and vigorously secreting more inflammatory cytokines and chemokines.

In contrast, alternatively activated macrophages, also known as M2 polarization , have tissue regenerative, pro-fibrotic, and anti-inflammatory characteristics. Various subsets of this phenotype are induced by a combination of cytokines such as interleukin-4 (IL-4), IL-10, IL-13, transforming growth factor beta (TGF-β), glucocorticoids or macrophage colony-stimulating factor (M-CSF) [25]. For example, macrophages treated with IL-4 and IL-13 produce minimal amounts of pro-inflammatory cytokines, and their other secretory products stimulate cell growth and proliferation as well as collagen formation. Hence, M1 and M2 polarization are considered to represent the opposite ends of the continuum of macrophage phenotypes [16, 26]. Whereas M1 polarized macrophages predominate in a strong pro-inflammatory phase at an early stage of an inflammation, M2 polarization gradually takes over when the intrusive agents become cleared. The tissue under inflammatory signaling likely contains macrophages with mixed phenotypes, and crosstalk between these cells enables a proper healing process and the resolution of the inflammation.

2.3 Interaction Between Macrophages and Orthopedic Biomaterials

Tissue injury caused by surgical insertion of an orthopedic implant initially activates the immune system, but with time, the implant itself mediates inflammation as a foreign body [27]. The initial recognition of a biomaterial and the tissue trauma caused by the implantation is primarily performed by resident macrophages, which subsequently become activated to a pro-inflammatory phenotype and initiate an inflammatory response. Since many orthopedic implants, such as joint replacements, are generally designed for permanent tissue and bone integration, they are biologically non-degradable, and might provide a constant stimulus for macrophage activation. In particular, the release of particulate materials of a phagocytosable size (<10 μm in diameter) has proven to provide a constant stimulus for inflammatory macrophage activation; these phagocytosable particles have been shown to induce endosomal damage with subsequent activation of intracellular danger sensing mechanisms [28, 29]. A prolonged presence of M1 macrophages leads to an increased inflammatory status, fibrosis, and granulomatous tissue around the implant—a condition called the chronic foreign body reaction [11, 30].

The long-lasting inflammatory events at the bone-implant interface have been observed to significantly affect the bone repair process and cause implant failures via osteolysis [31, 32]. At the cellular level, pro-inflammatory mediators such as TNF-α favor bone resorption over bone formation by increasing the production of Receptor Activator of NF-κB Ligand (RANKL) and decreasing the production of osteoprotegerin (OPG) resulting in an altered RANKL/OPG ratio [33]. RANKL efficiently stimulates the activation and proliferation of osteoclast precursors whereas OPG acts as a decoy receptor inhibiting RANKL signaling. Sustained inflammation thus drives osteoclast formation and ultimately failure of the implant.

As implant-mediated inflammation closely involves adverse tissue reactions and bone regeneration, novel approaches for biomaterial engineering are being developed: a new generation of orthopedic biomaterials should be able to modulate the immune environment in order to favor osseointegration of the implant [34]. This immunomodulating strategy aims to extend the lifespan of the implant by minimizing the destructive and maximizing the regenerative effects of the immune response induced by the implant.

2.4 Modulation of Macrophage-Mediated Pro-Inflammatory Response

Macrophages are a prime target for immunomodulation in the application of orthopedic biomaterials. This is not only because these cells play an essential role in initiating and regulating the implant-mediated immune responses, but also because of their considerable heterogeneity and plasticity enable the modulation of their function [16, 30]. Methods controlling macrophage activation could discourage increases in the pro-inflammatory signaling, avoid excess fibrosis, and prevent bone loss around the implants. Thus, new therapeutic interventions are being pursued with the purpose of controlling chronic inflammation associated with implant materials by modulating macrophage polarization and thus their secretory products. Whereas continuous M1 activation impairs integration of the implant, signals that suppress the pro-inflammatory effects and support M2 polarization have emerged as an attractive means to facilitate implant integration [35, 36].

Several different strategies for macrophage-targeted immunomodulation around implants have been developed (Fig. 1) [37]. Since the degree of an implant-mediated immune reaction depends on the biomaterial characteristics, beneficial effects on macrophage function and implant integration may be achieved by modifying the physical and chemical properties of the biomaterial. For instance, the specific surface structure of the implant material and the amount of wear products accumulating in the surrounding tissues are important variables that determine the type of macrophage activation. Surface topography of the implant can be optimized for porosity, roughness, hydrophilicity, and the ability to produce wear particles in order to decrease initial monocyte adhesion and activation [34]. These micro- and nanoscale material characteristics largely determine the folding of absorbed proteins on the implant and consequent presentation of bioactive sites for macrophages. Moreover, TGF-β and PDGF directly modulate macrophage function and chemotaxis during wound healing without a foreign body and may play a similar role in peri-implant biology [38]. Implants loaded with these molecules could thus theoretically promote tissue and bone regeneration both directly and indirectly.

Fig. 1
figure 1

Strategies to modulate the innate inflammatory reactions against orthopedic biomaterials. 1. Optimize biomaterial characteristics, e.g. surface roughness, porosity, and generation of wear particles , 2. Delivery of macrophage polarizing cytokines to drive the anti-inflammatory M2 macrophage polarization, 3. Inhibition of pro-inflammatory cytokines such as TNF-α, 4. Blockade of the transcription factor NF-κB, 5. Inhibiting chemokines such as CCL2 to suppress monocyte recruitment, and 6. Coupling biomaterials with anti-inflammatory and bioactive molecules

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Incorporation of immunomodulatory agents into the implant constitutes another major strategy to modulate innate immune reactions. For example, macrophage-mediated inflammation could be controlled by the local release of M2 polarizing cytokines IL-4, IL-10, or IL-13 [35]. In particular, IL-4 has shown great potential to increase implant integration to bone and mitigate wear particle-induced inflammation in animal models [39,40,41]. Delivery of IL-4 alters the function of local M1 activated macrophages towards an anti-inflammatory M2 phenotype and dramatically reduces the production of pro-inflammatory cytokines. In addition, IL-4 has anti-osteoclastogenic effects that might promote osseointegration of the implant. IL-10 and IL-13 possess similar immune-regulatory properties. These cytokines have been reported to inhibit the expression of pro-inflammatory cytokines in macrophages and drive M2 activation [25]. Several studies that used a murine subcutaneous implantation model rather than delivery of wear particles demonstrated that the release of IL-4 attracts M2 macrophages and modulates the inflammatory response to improve the implant integration [42,43,44]. Interestedly, sequential delivery of M1 and M2 polarizing factors mimicking the natural course of tissue regeneration enhanced implant vascularization. The anti-inflammatory phenotypic switch promoted implant integration also by diminishing the formation of a fibrous capsule and increasing the quality of remodeled collagen around the implant. Further studies are needed to investigate the full potential of M2 polarizing cytokines in orthopedic applications.

In addition to favoring M2 polarization, improved tissue healing around an implant could potentially be achieved by directly inhibiting pro-inflammatory signals. For example, TNF-α, one of the most potent pro-inflammatory cytokines, promotes M1 macrophage polarization, enhances fibrosis, inhibits osteoblast differentiation, induces osteoclast formation, and thus mediates osteolysis around orthopedic implants [45, 46]. Blocking these effects by anti-TNF-α therapy provides a means to modulate implant-induced immune responses. Etanercept, a decoy receptor for TNF-α, was shown to mitigate wear particle-induced cytokine production from macrophages and reduce bone resorption in animals but was not effective in a small clinical trial [47, 48]. Similar results were obtained using an antisense oligonucleotide targeting to mouse TNF-α mRNA in a murine calvarial model [49]. However, blocking the effect of only one pro-inflammatory mediator among the complicated signal network may not be enough to prevent osteolysis in the long term. The compensatory actions of other pro-inflammatory cytokines, such as IL-1β and IL-6, could maintain an inflammatory status in the peri-implant tissue in the absence of TNF-α signaling. A combination of locally delivered cytokine inhibitors might thus prove to be more effective.

Transcription factor NF-κB serves as another target for immunomodulation in the context of implant-mediated immune response [35]. This transcription factor functions as a key regulator of multiple inflammatory cytokines and chemokines in macrophages, and becomes active as a result of a relevant PRR stimulus [10, 50]. Moreover, NF-κB mediates the RANKL signaling, which is integral for osteoclast differentiation and activation. Thus, inhibition of this transcription factor offers an intriguing possibility to attenuate the biomaterial-induced inflammation and osteolysis. This inhibitory effect has been demonstrated using a decoy oligodeoxynucleotide (ODN) that competitively binds NF-κB in vitro and in vivo with polyethylene particles as the adverse inflammatory stimulus; the suppression of intracellular signaling in macrophages resulted in less cytokine expression and osteoclast activation [51, 52]. NF-κB decoy may also suppress the production of chemokines essential for monocyte recruitment.

Preventing the continued recruitment of immune cells to the bone-implant interface could mitigate the inflammatory reaction and periprosthetic bone loss and constitutes another strategy for immunomodulation. Indeed, a chemokine directed immunomodulatory method was recently established using a mutant C-C motif chemokine ligand 2 (CCL2) protein to inhibit CCL2 signaling [53, 54]. Anti-CCL2 therapy suppressed macrophage recruitment to the implant in a murine model and prevented wear particle induced inflammation and bone loss.

Lastly, orthopedic biomaterials can be coupled with anti-inflammatory drugs such as glucocorticoids. These drugs elicit an alternative macrophage phenotype with an increased ability to recognize and scavenge dying cells. These macrophages suppress the production of numerous inflammatory mediators such as pro-inflammatory cytokines, chemokines, prostaglandins, leukotrienes, and proteolytic enzymes, whereas an enhanced expression of anti-inflammatory cytokine IL-10 has been reported. Other bioactive molecules that can also be considered as immunomodulatory, include TGF-β, VEGF, and PDGF [27]. These growth factors tightly regulate the healing process by targeting fibroblasts and endothelial cells, rather than macrophages. Moreover, TGF-β and PDGF directly modulate macrophage function and chemotaxis at least during wound healing without a foreign body [38]. Implants loaded with these molecules could thus potentially also promote bone regeneration and implant integration either directly or indirectly.

3 Sequential Modulation of Inflammatory Response for Optimal Bone Regeneration/Osseointegration

3.1 Essential Role of Acute Inflammation in Bone Regeneration

Determination of the appropriate timeframe of immunomodulation is critical for optimizing their application as orthopedic biomaterials. Acute phase inflammation is crucial for proper bone repair after trauma. Impairing early inflammatory conditions in a murine fracture model resulted in diminished stem cell recruitment and differentiation, fracture callus formation, and overall bone growth [55,56,57,58]. The inflammatory phase sparks the repair cascade by initiating angiogenesis, recruiting and stimulating the differentiation of mesenchymal stem cells (MSCs) , and encouraging extracellular matrix synthesis [59,60,61].

Specific cytokines appear to be tied to the inflammatory phase of bone repair, namely TNF-α and IL-1 [62]. TNF-α and IL-1 are more commonly known for mediating foreign body reactions that can result in impaired tissue function and rejection of prosthetic implants [63]. Gerstenfeld et al. showed that a reduction in TNF-α signaling results in improper formation of fracture callus and delayed endochondral and intramembranous bone formation [56]. The key difference between pathological and therapeutic inflammation is that the latter is highly regulated, both in intensity, duration, and timing to provide a foundation for healing [62].

3.2 Transition of Macrophage Polarization Status for Optimal Bone Formation

Macrophage polarization status also plays a critical role in bone regeneration. M1 macrophages, despite releasing inflammatory cytokines, are highly angiogenic, stimulate early mineralization by MSCs, and support overall bone healing [64,65,66,67]. M2 macrophages, on the other hand, secrete anti-inflammatory cytokines such as IL-10 and IL-1Ra and have been associated with enhanced bone formation [68,69,70]. This proves to be a delicate balance that can result in failed bone regeneration if tipped too far one way or another. As such, the interplay between M1- and M2-dominated microenvironments is one that provides interesting avenues through which to pursue new immune-modulatory therapies.

After an injury, the acute inflammatory phase has been shown to last from 3–7 days before the anti-inflammatory phase begins to exert its longer-lasting influence [43, 71, 72]. Proper timing of the transition between the two phases is crucial to optimal bone regeneration. Indeed, Loi et al. showed that transition from M1 to M2-like macrophages at 72 hours resulted in significantly increased osteogenesis by MC3T3 osteoprogenitors in a co-culture model. Further studies exploring the mechanisms and temporal modulation of the M1 to M2 transition are warranted, as this could provide a prime early target for improved bone repair and implant integration.

The task of stimulating M1 macrophages to transition to M2 macrophages to enhance bone regeneration is one that is currently under investigation. One possible method is to utilize a controlled release system to maintain a short period of M1, followed by a transition to M2 polarization via cytokines such as IFN-γ, IL-4, and IL-10. Kumar et al. reported the development of a multi-domain peptide hydrogel that delivered IL-4 and CCL2 in a biphasic manner. This biphasic, sustained delivery was able to modulate both non-polarized (M0) and M1 macrophages towards an M2-like phenotype [73]. Finally, Spiller et al. utilized a decellularized bone scaffold to release IFN- γ over the first 3 days of repair, along with release of IL-4 over the first 6 days. The bone scaffolds were able to spur polarization towards an M2 phenotype in vitro and led to enhanced angiogenesis in an in vivo subcutaneous murine model [43]. The modulation of M1 to M2 is not limited to cytokine release systems; Rostam et al. has shown that physical and chemical modifications to biomaterial surfaces alone can shift the macrophage polarization towards M1 or M2 [74, 75].

4 Application of Immunomodulating Reagents on Orthopedic Biomaterials

The delivery method of various immunomodulating reagents to enhance the performance of orthopedic biomaterials is dependent on the physical and biological characteristics of the agent. The therapeutic molecules with different biological features including molecular size, hydrophilic/hydrophobic, stability (degradation rate), effective dose, and the optimal administration time points determine the optimal strategy for drug delivery. Different materials used for orthopedic implants can also influence the drug delivery efficiency. For example, the absorption of small peptides on the metal surface is ineffective compared to the application on a polymeric surface.

Surface coating and drug releasing materials are an interesting strategy to modulate the tissue environment surrounding orthopedic implants. The various strategies to apply these bioactive coating on orthopedic implants including hydrogel, layer-by-layer, and immobilization have been summarized comprehensively in other reviews [76, 77]. Agarwal et al. summarized strategies to enhance osseointegration of orthopedic implants by biomolecules such as growth factors, with similar delivery methods being potentially applicable for the delivery of immunomodulating reagents [78]. In the following section, the immunomodulating candidates are classified into four categories including: (1) protein, (2) nucleic acid, (3) small molecule, and (4) cell-based therapies (Table 1). The current development of administration strategies and the therapeutic effects in the application of orthopedic biomaterials are discussed.

Table 1 Delivery strategies for immunomodulating biomolecules
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4.1 Protein-Based Biomolecules

The size of the immunomodulating protein determines the biomaterial coating strategy and release pattern. Large proteins such as antibodies or fusion protein inhibitors (~150 kDa) targeting pro-inflammatory cytokines or the associated receptors can be coated with hydrogels with larger pore sizes. Anti-TNFα antibodies conjugated with a hyaluronic acid hydrogel was applied to a burn wound and demonstrated an inhibitory effect on inflammation [79]. Direct treatment of a soluble TNFα inhibitor (Etanercept) mitigated wear particle-induced osteolysis [47]. However, no significant difference was observed between Etanercept and placebo-treated patients with acetabular loosening [48]. The results may be due to the limited number of patients, or the compensatory effects of other pro-inflammatory cytokines.

Small proteins including anti-inflammatory cytokines IL-4, IL-10, and IL-13 (ranging from 15 to 21 kDa) can be applied via a hydrogel with smaller pore size or layer-by-layer coating. A nanometer thickness IL-4 eluting layer-by-layer coated polypropylene mesh showed improved implant integration and enhanced M2 macrophage polarization in a subcutaneous implantation murine model [44]. Further validation is required to demonstrate the potential to improve osseointegration of IL-4 eluting bone implants. Another example of this protein delivery approach demonstrated that titanium rods coated with mutant CCL2 protein (7ND) with a layer-by-layer technique mitigated polyethylene wear particle-induced osteolysis in a murine femoral infusion model (See Sect. 2.4 for details) [53].

Small peptides with anti-microbial and immunomodulating activity have recently been identified [80, 81]. Compared to whole protein biomolecules, a higher concentration of small peptides could be potentially applied onto or within biomaterials and thus increase the immunomodulating efficiency [76]. Inhibition of NF-κB activation by a small peptide termed NEMO-binding domain peptide suppressed poly(methyl methacrylate) (PMMA) induced osteoclastogenesis and osteolysis in a murine calvarial model, yet the modulation of an inflammatory response was not characterized [82].

4.2 Nucleic Acid

Gene therapy is mediated through the delivery of nucleic acid-based biomolecules, including plasmid DNA, RNA interference (RNAi), micro-RNA, and ODN, to express proteins or modulate gene expression in the target cells. Delivery of naked nucleic acid is inefficient due to low cell attachment/uptake and rapid nuclease-mediated degradation. Therefore, viral and non-viral vectors are utilized to mediate the delivery of anti-inflammatory genes or silence pro-inflammatory gene expression in vivo. Viral vectors are efficient in transducing target gene expression ex vivo and thus are effective tools to induce gene expression in cell-based therapy (see Sect. 4.4). In contrast, the immunogenicity and potential cytotoxicity effects of viral vectors may limit their direct translational use in vivo. Non-viral vectors, including calcium phosphate, liposomes, nano-hydroxyapatite [83], chitosan [84, 85], polyethyleneimine [86], and dendrimer [87], have lower immunogenicity and cytotoxicity but also lower transfection efficiency in vivo. Raftery et al. summarized the current development of delivering nucleic acid-based biomolecules in orthopedic biomaterials [88].

The combination of scaffolds and gene delivery vectors is a highly promising strategy for prolonged immunomodulation and controlled released of nucleic acid-based biomolecules. Previous studies showed that a combination of collagen or poly-lactic-co-glycolic acid (PLGA) scaffolds with viral or non-viral vectors delivered plasmid DNA or RNAi enhances tissue regeneration [89,90,91,92,93,94]. The therapeutic potential of immunomodulation using this strategy remains to be investigated in inflammatory bone disorders. Decoy ODN can be taken up by the cellular receptor in a sequence-specific manner [95]. The administration of decoy ODN without delivery vectors via local infusion was shown to mitigate orthopedic wear particle-induced osteolysis [51].

4.3 Small Molecules

Small molecule drugs have several advantages in clinical applications including the efficient administration and relative low cost for large-scale production. Steroids and molecular kinase inhibitors are potent anti-inflammatory small molecules that could be applied to orthopedic biomaterials. Signal transduction pathways including NF-κB and MAP kinase are crucial for the regulation of inflammatory responses [50, 96] and periprosthetic osteolysis [10, 97]. Titanium particles have induced VEGF expression and increased macrophage chemotactic activity in primary human macrophages, which was inhibited by MAPK kinase inhibitor PD98059 [98].

A daily injection of N- (2-hydroxypropyl) methacrylamide copolymer-dexamethasone conjugate mitigated osteolysis in the murine femur infused with PMMA particles [99]. Systemic bone loss was not observed in the conjugated dexamethasone injected mice. Several advanced drug-delivery strategies have been developed to apply dexamethasone in pre-clinical inflammatory disease models [100,101,102]. An inflammation-targeting hydrogel generated from ascorbyl palmitate was developed to deliver dexamethasone in an inflammatory bowel disease model [103]. While these drug delivery strategies have shown promise for the treatment of inflammatory disorders, the application in orthopedic biomaterials remains to be examined.

4.4 Cell-Based Therapy

MSCs-based therapy has been applied to bone tissue engineering and inflammatory disorders. The ability to modulate innate [104, 105] and adaptive immune responses [106] further underscored its translational potential to modulate inflammation associated with orthopedic biomaterials. Moreover, MSCs can serve as gene expression carriers to secrete immunomodulating cytokines such as IL-4 or IL-10 [107, 108]. The applications of MSC-based therapy in bone regeneration and immunomodulation are discussed in other reviews [109,110,111]. The following section focuses on scaffold and delivery strategies in MSC-based therapy.

MSC based therapy can be administrated through local implantation or systemic delivery. Natural and synthetic scaffolds are crucial for the local administration of MSC-based therapy by providing the appropriate mechanical strength and cell viability [112]. Commonly used natural scaffolds in bone tissue engineering include collagen hyaluronic acid fibrin and poly(ε-caprolactone)/poly(vinyl alcohol)/chitosan-associated hybrid scaffolds. However purity issues and poor mechanical properties limit the application of natural scaffolds. Synthetic scaffolds including PLGA polyglycolic acid (PGA) and poly-l-lactic acid (PLA) enable the precise control of mechanical properties and stability of the scaffold to further enhance therapeutic efficiency. For example a macroporous and highly flexible gelatin-based scaffold with a microribbon-like structure has recently been demonstrated to increase MSC proliferation and bone regeneration [113]. However the biocompatibility of the synthetic scaffold remains a concern since degradation products could initiate inflammatory responses [114]. The systemic delivery of MSCs provides an alternative strategy of minimally invasive procedures to patients with orthopedic implants. Though MSCs can naturally migrate into inflammatory sites conjugating with antibodies targeting bone or inflammation-associated molecules can further enhance their homing efficiency [115, 116].

5 Conclusion

Transient acute inflammation is closely associated with successful osseointegration and bone regeneration in orthopedic biomaterial implantation. The transition between the pro-inflammatory M1 and anti-inflammatory M2 macrophage phenotypes has been shown to be a key step in bone regeneration. Alternatively, chronic inflammatory bone diseases associated with implants often exhibit excessive pro-inflammatory macrophage infiltration and the generation of wear particles . The combination of bone regenerating scaffolds and controlled drug releasing systems has great potential for advancing clinical applications of orthopedic biomaterials for a variety of conditions including aseptic loosening, osteonecrosis, and fracture nonunion. Taken together, optimizing the timing and efficacy of the innate immune reaction provide a promising approach to harness the inflammatory response for therapeutic applications of orthopedic biomaterials.