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Effect of porous orthopaedic implant material and structure on load sharing with simulated bone ingrowth: A finite element analysis comparing titanium and PEEK.

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Effect of porous orthopaedic implant material and structure on load sharing with simulated bone ingrowth: A finite element analysis comparing titanium and PEEK.

J Mech Behav Biomed Mater. 2018 Apr;80:68-76

Authors: Carpenter RD, Klosterhoff BS, Torstrick FB, Foley KT, Burkus JK, Lee CSD, Gall K, Guldberg RE, Safranski DL

Abstract
Osseointegration of load-bearing orthopaedic implants, including interbody fusion devices, is critical to long-term biomechanical functionality. Mechanical loads are a key regulator of bone tissue remodeling and maintenance, and stress-shielding due to metal orthopaedic implants being much stiffer than bone has been implicated in clinical observations of long-term bone loss in tissue adjacent to implants. Porous features that accommodate bone ingrowth have improved implant fixation in the short term, but long-term retrieval studies have sometimes demonstrated limited, superficial ingrowth into the pore layer of metal implants and aseptic loosening remains a problem for a subset of patients. Polyether-ether-ketone (PEEK) is a widely used orthopaedic material with an elastic modulus more similar to bone than metals, and a manufacturing process to form porous PEEK was recently developed to allow bone ingrowth while preserving strength for load-bearing applications. To investigate the biomechanical implications of porous PEEK compared to porous metals, we analyzed finite element (FE) models of the pore structure-bone interface using two clinically available implants with high (> 60%) porosity, one being constructed from PEEK and the other from electron beam 3D-printed titanium (Ti). The objective of this study was to investigate how porous PEEK and porous Ti mechanical properties affect load sharing with bone within the porous architectures over time. Porous PEEK substantially increased the load share transferred to ingrown bone compared to porous Ti under compression (i.e. at 4 weeks: PEEK = 66%; Ti = 13%), tension (PEEK = 71%; Ti = 12%), and shear (PEEK = 68%; Ti = 9%) at all time points of simulated bone ingrowth. Applying PEEK mechanical properties to the Ti implant geometry and vice versa demonstrated that the observed increases in load sharing with PEEK were primarily due to differences in intrinsic elastic modulus and not pore architecture (i.e. 4 weeks, compression: PEEK material/Ti geometry = 53%; Ti material/PEEK geometry = 12%). Additionally, local tissue energy effective strains on bone tissue adjacent to the implant under spinal load magnitudes were over two-fold higher with porous PEEK than porous Ti (i.e. 4 weeks, compression: PEEK = 784 ± 351 microstrain; Ti = 180 ± 300 microstrain; and 12 weeks, compression: PEEK = 298 ± 88 microstrain; Ti = 121 ± 49 microstrain). The higher local strains on bone tissue in the PEEK pore structure were below previously established thresholds for bone damage but in the range necessary for physiological bone maintenance and adaptation. Placing these strain magnitudes in the context of literature on bone adaptation to mechanical loads, this study suggests that porous PEEK structures may provide a more favorable mechanical environment for bone formation and maintenance under spinal load magnitudes than currently available porous 3D-printed Ti, regardless of the level of bone ingrowth.

PMID: 29414477 [PubMed – in process]

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Decorin-containing collagen hydrogels as dimensionally stable scaffolds to study the effects of compressive mechanical loading on angiogenesis.

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Decorin-containing collagen hydrogels as dimensionally stable scaffolds to study the effects of compressive mechanical loading on angiogenesis.

MRS Commun. 2017 Sep;7(3):466-471

Authors: Ruehle MA, Krishnan L, LaBelle SA, Willett NJ, Weiss JA, Guldberg RE

Abstract
Angiogenesis is a critical component during wound healing, and the process is sensitive to mechanical stimuli. Current in vitro culture environments used to investigate three-dimensional microvascular growth often lack dimensional stability and the ability to withstand compression. We investigated the ability of decorin, a proteoglycan known to modulate collagen fibrillogenesis, incorporated into a collagen hydrogel to increase construct dimensional stability while maintaining vascular growth. Decorin did not affect microvascular growth parameters, while increasing the compressive modulus of collagen gels and significantly reducing the contraction of 3% collagen gels after 16 days in culture.

PMID: 29450108 [PubMed]

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Clinical potential of implantable wireless sensors for orthopedic treatments.

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Clinical potential of implantable wireless sensors for orthopedic treatments.

Expert Rev Med Devices. 2018 Apr;15(4):255-264

Authors: Karipott SS, Nelson BD, Guldberg RE, Ong KG

Abstract
INTRODUCTION: Implantable wireless sensors have been used for real-time monitoring of chemicals and physical conditions of bones, tendons and muscles to diagnose and study orthopedic diseases and injuries. Due to the importance of these sensors in orthopedic care, a critical review, which not only analyzes the underlying technologies but also their clinical implementations and challenges, will provide a landscape view on their current state and their future clinical role. Areas covered: By conducting an extensive literature search and following the leaders of orthopedic implantable wireless sensors, this review covers the battery-powered and battery-free wireless implantable sensor technologies, and describes their implementation for hips, knees, spine, and shoulder stress/strain monitoring. Their advantages, limitations, and clinical challenges are also described. Expert commentary: Currently, implantable wireless sensors are mostly limited for scientific investigations and demonstrative experiments. Although rapid advancement in sensors and wireless technologies will push the reliability and practicality of these sensors for clinical realization, regulatory constraints and financial viability in medical device industry may curtail their continuous adoption for clinical orthopedic applications. In the next five years, these sensors are expected to gain increased interest from researchers, but wide clinical adoption is still unlikely.

PMID: 29558820 [PubMed – indexed for MEDLINE]

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Biological evaluation and finite-element modeling of porous poly(para-phenylene) for orthopaedic implants.

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Biological evaluation and finite-element modeling of porous poly(para-phenylene) for orthopaedic implants.

Acta Biomater. 2018 May;72:352-361

Authors: Ahn H, Patel RR, Hoyt AJ, Lin ASP, Torstrick FB, Guldberg RE, Frick CP, Carpenter RD, Yakacki CM, Willett NJ

Abstract
Poly(para-phenylene) (PPP) is a novel aromatic polymer with higher strength and stiffness than polyetheretherketone (PEEK), the gold standard material for polymeric load-bearing orthopaedic implants. The amorphous structure of PPP makes it relatively straightforward to manufacture different architectures, while maintaining mechanical properties. PPP is promising as a potential orthopaedic material; however, the biocompatibility and osseointegration have not been well investigated. The objective of this study was to evaluate biological and mechanical behavior of PPP, with or without porosity, in comparison to PEEK. We examined four specific constructs: 1) solid PPP, 2) solid PEEK, 3) porous PPP and 4) porous PEEK. Pre-osteoblasts (MC3T3) exhibited similar cell proliferation among the materials. Osteogenic potential was significantly increased in the porous PPP scaffold as assessed by ALP activity and calcium mineralization. In vivo osseointegration was assessed by implanting the cylindrical materials into a defect in the metaphysis region of rat tibiae. Significantly more mineral ingrowth was observed in both porous scaffolds compared to the solid scaffolds, and porous PPP had a further increase compared to porous PEEK. Additionally, porous PPP implants showed bone formation throughout the porous structure when observed via histology. A computational simulation of mechanical push-out strength showed approximately 50% higher interfacial strength in the porous PPP implants compared to the porous PEEK implants and similar stress dissipation. These data demonstrate the potential utility of PPP for orthopaedic applications and show improved osseointegration when compared to the currently available polymeric material.
STATEMENT OF SIGNIFICANCE: PEEK has been widely used in orthopaedic surgery; however, the ability to utilize PEEK for advanced fabrication methods, such as 3D printing and tailored porosity, remain challenging. We present a promising new orthopaedic biomaterial, Poly(para-phenylene) (PPP), which is a novel class of aromatic polymers with higher strength and stiffness than polyetheretherketone (PEEK). PPP has exceptional mechanical strength and stiffness due to its repeating aromatic rings that provide strong anti-rotational biaryl bonds. Furthermore, PPP has an amorphous structure making it relatively easier to manufacture (via molding or solvent-casting techniques) into different geometries with and without porosity. This ability to manufacture different architectures and use different processes while maintaining mechanical properties makes PPP a very promising potential orthopaedic biomaterial which may allow for closer matching of mechanical properties between the host bone tissue while also allowing for enhanced osseointegration. In this manuscript, we look at the potential of porous and solid PPP in comparison to PEEK. We measured the mechanical properties of PPP and PEEK scaffolds, tested these scaffolds in vitro for osteocompatibility with MC3T3 cells, and then tested the osseointegration and subsequent functional integration in vivo in a metaphyseal drill hole model in rat tibia. We found that PPP permits cell adhesion, growth, and mineralization in vitro. In vivo it was found that porous PPP significantly enhanced mineralization into the construct and increased the mechanical strength required to push out the scaffold in comparison to PEEK. This is the first study to investigate the performance of PPP as an orthopaedic biomaterial in vivo. PPP is an attractive material for orthopaedic implants due to the ease of manufacturing and superior mechanical strength.

PMID: 29563069 [PubMed – in process]

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Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis.

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Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis.

Biomater Sci. 2018 May 01;6(5):1159-1167

Authors: Tellier LE, Treviño EA, Brimeyer AL, Reece DS, Willett NJ, Guldberg RE, Temenoff JS

Abstract
As a potential treatment for osteoarthritis (OA), we have developed injectable and hydrolytically degradable heparin-based biomaterials with tunable sulfation for the intra-articular delivery of tumor necrosis factor-alpha stimulated gene-6 (TSG-6), a protein known to inhibit plasmin which may degrade extracellular matrix within OA joints. We first assessed the effect of heparin sulfation on TSG-6 anti-plasmin activity and found that while fully sulfated (Hep) and heparin desulfated at only the N position (Hep-N) significantly enhanced TSG-6 bioactivity in vitro, fully desulfated heparin (Hep-) had no effect, indicating that heparin sulfation plays a significant role in modulating TSG-6 bioactivity. Next, TSG-6 loaded, degradable 10 wt% Hep-N microparticles (MPs) were delivered via intra-articular injection into the knee at 1, 7, and 15 days following medial meniscal transection (MMT) injury in a rat model. After 21 days, cartilage thickness, volume, and attenuation were significantly increased with soluble TSG-6, indicating degenerative changes. In contrast, no significant differences were observed with TSG-6 loaded MP treatment, demonstrating that TSG-6 loaded MPs reduced cartilage damage following MMT injury. Ultimately, our results indicate that Hep-N can enhance TSG-6 anti-plasmin activity and that Hep-N-based biomaterials may be an effective method for TSG-6 delivery to treat OA.

PMID: 29564448 [PubMed – indexed for MEDLINE]

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Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing.

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Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing.

Proc Natl Acad Sci U S A. 2018 05 29;115(22):E4960-E4969

Authors: Johnson CT, Wroe JA, Agarwal R, Martin KE, Guldberg RE, Donlan RM, Westblade LF, García AJ

Abstract
Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat Staphylococcus aureus infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. Lysostaphin encapsulation within this synthetic hydrogel maintained enzyme stability and activity. Lysostaphin-delivering hydrogels exhibited enhanced antibiofilm activity compared with soluble lysostaphin. Lysostaphin-delivering hydrogels eradicated S. aureus infection and outperformed prophylactic antibiotic and soluble lysostaphin therapy in a murine model of femur fracture. Analysis of the local inflammatory response to infections treated with lysostaphin-delivering hydrogels revealed indistinguishable differences in cytokine secretion profiles compared with uninfected fractures, demonstrating clearance of bacteria and associated inflammation. Importantly, infected fractures treated with lysostaphin-delivering hydrogels fully healed by 5 wk with bone formation and mechanical properties equivalent to those of uninfected fractures, whereas fractures treated without the hydrogel carrier were equivalent to untreated infections. Finally, lysostaphin-delivering hydrogels eliminate methicillin-resistant S. aureus infections, supporting this therapy as an alternative to antibiotics. These results indicate that lysostaphin-delivering hydrogels effectively eliminate orthopedic S. aureus infections while simultaneously supporting fracture repair.

PMID: 29760099 [PubMed – indexed for MEDLINE]

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Aggregate mesenchymal stem cell delivery ameliorates the regenerative niche for muscle repair.

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Aggregate mesenchymal stem cell delivery ameliorates the regenerative niche for muscle repair.

J Tissue Eng Regen Med. 2018 Aug;12(8):1867-1876

Authors: Ruehle MA, Stevens HY, Beedle AM, Guldberg RE, Call JA

Abstract
Duchenne muscular dystrophy is a severe muscle wasting disease due to the absence of the dystrophin protein from the muscle cell membrane, which renders the muscle susceptible to continuous damage. In Duchenne muscular dystrophy patients, muscle weakness, together with cycles of degeneration/regeneration and replacement with noncontractile tissue, limit mobility and lifespan. Because the loss of dystrophin results in loss of polarity and a reduction in the number of self-renewing satellite cells, it is postulated that these patients could achieve an improved quality of life if delivered cells could restore satellite cell function. In this study, we used both an established myotoxic injury model in wild-type (WT) mice and mdx mice alone (spontaneous muscle damage). Single (SC) and aggregated (AGG) mesenchymal stem cells (MSCs) were injected into the gastrocnemius muscles 4 hr after injury (WT mice). The recovery of peak isometric torque was longitudinally assessed over 5 weeks, with earlier takedowns for histological assessment of healing (fibre cross-section area and central nucleation) and MSC retention. AGG-treated WT mice had significantly greater torque recovery at Day 14 than SC or saline-treated mice and a greater CSA at Day 10, compared with SC/saline. AGG-treated mdx mice had a greater peak isometric torque compared with SC/saline. In vitro immunomodulatory factor secretion of AGG-MSCs was higher than SC-MSCs for all tested growth factors with the largest difference observed in hepatocyte growth factor. Future studies are necessary to pair immunomodulatory factor secretion with functional attributes, to better predict the potential therapeutic value of MSC treatment modalities.

PMID: 29774991 [PubMed – in process]

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Dynamic mass spectrometry probe for electrospray ionization mass spectrometry monitoring of bioreactors for therapeutic cell manufacturing.

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Dynamic mass spectrometry probe for electrospray ionization mass spectrometry monitoring of bioreactors for therapeutic cell manufacturing.

Biotechnol Bioeng. 2018 Sep 10;:

Authors: Chilmonczyk MA, Kottke PA, Stevens HY, Guldberg RE, Fedorov AG

Abstract
Large-scale manufacturing of therapeutic cells requires bioreactor technologies with online feedback control enabled by monitoring of secreted biomolecular critical quality attributes (CQAs). Electrospray ionization mass spectrometry (ESI-MS) is a highly sensitive label-free method to detect and identify biomolecules, but requires extensive sample preparation before analysis, making online application of ESI-MS challenging. We present a microfabricated, monolithically integrated device capable of continuous sample collection, treatment, and direct infusion for ESI-MS detection of biomolecules in high-salt solutions. The dynamic mass spectrometry probe (DMSP) uses a microfluidic mass exchanger to rapidly condition samples for online MS analysis by removing interfering salts, while concurrently introducing MS signal enhancers to the sample for sensitive biomolecular detection. Exploiting this active conditioning capability increases MS signal intensity and signal-to-noise ratio. As a result, sensitivity for low-concentration biomolecules is significantly improved, and multiple proteins can be detected from chemically complex samples. Thus, the DMSP has significant potential to serve as an enabling portion of a novel analytical tool for discovery and monitoring of CQAs relevant to therapeutic cell manufacturing.

PMID: 30199089 [PubMed – as supplied by publisher]

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Porous PEEK improves the bone-implant interface compared to plasma-sprayed titanium coating on PEEK.

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Porous PEEK improves the bone-implant interface compared to plasma-sprayed titanium coating on PEEK.

Biomaterials. 2018 Dec;185:106-116

Authors: Torstrick FB, Lin ASP, Potter D, Safranski DL, Sulchek TA, Gall K, Guldberg RE

Abstract
Polyether-ether-ketone (PEEK) is one of the most common materials used for load-bearing orthopaedic devices due to its radiolucency and favorable mechanical properties. However, current smooth-surfaced PEEK implants can lead to fibrous encapsulation and poor osseointegration. This study compared the in vitro and in vivo bone response to two smooth PEEK alternatives: porous PEEK and plasma-sprayed titanium coatings on PEEK. MC3T3 cells were grown on smooth PEEK, porous PEEK, and Ti-coated PEEK for 14 days and assayed for calcium content, osteocalcin, VEGF and ALP activity. Osseointegration was investigated by implanting cylindrical implants into the proximal tibiae of male Sprague Dawley rats for 8 weeks. Bone-implant interfaces were evaluated using μCT, histology and pullout testing. Cells on porous PEEK surfaces produced more calcium, osteocalcin, and VEGF than smooth PEEK and Ti-coated PEEK groups. Bone ingrowth into porous PEEK surfaces was comparable to previously reported porous materials and correlated well between μCT and histology analysis. Porous PEEK implants exhibited greater pullout force, stiffness and energy-to-failure compared to smooth PEEK and Ti-coated PEEK, despite Ti-coated PEEK exhibiting a high degree of bone-implant contact. These results are attributed to increased mechanical interlocking of bone with the porous PEEK implant surface. Overall, porous PEEK was associated with improved osteogenic differentiation in vitro and greater implant fixation in vivo compared to smooth PEEK and Ti-coated PEEK. These results suggest that not all PEEK implants inherently generate a fibrous response and that topography has a central role in determining implant osseointegration.

PMID: 30236838 [PubMed – in process]

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Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine.

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Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine.

Adv Healthc Mater. 2018 Nov 06;:e1801000

Authors: Subbiah R, Guldberg RE

Abstract
Growth factors (GFs) are signaling molecules that direct cell development by providing biochemical cues for stem cell proliferation, migration, and differentiation. GFs play a key role in tissue regeneration, but one major limitation of GF-based therapies is dosage-related adverse effects. Additionally, the clinical applications and efficacy of GFs are significantly affected by the efficiency of delivery systems and other pharmacokinetic factors. Hence, it is crucial to design delivery systems that provide optimal activity, stability, and tunable delivery for GFs. Understanding the physicochemical properties of the GFs and the biomaterials utilized for the development of biomimetic GF delivery systems is critical for GF-based regeneration. Many different delivery systems have been developed to achieve tunable delivery kinetics for single or multiple GFs. The identification of ideal biomaterials with tunable properties for spatiotemporal delivery of GFs is still challenging. This review characterizes the types, properties, and functions of GFs, the materials science of widely used biomaterials, and various GF loading strategies to comprehensively summarize the current delivery systems for tunable spatiotemporal delivery of GFs aimed for tissue regeneration applications. This review concludes by discussing fundamental design principles for GF delivery vehicles based on the interactive physicochemical properties of the proteins and biomaterials.

PMID: 30398700 [PubMed – as supplied by publisher]

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