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Spanninga BJ, Hoelen TCA, Johnson S, Cheng B, Blokhuis TJ, Willems PC, Arts JJC. Clinical efficacy and safety of P-15 peptide enhanced bone graft substitute in surgical bone regenerative procedures in adult maxillofacial, spine, and trauma patients : a systematic literature review. Bone Joint Res 2025; 14:77-92. [PMID: 39901815 PMCID: PMC11795317 DOI: 10.1302/2046-3758.142.bjr-2024-0033.r2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2025] Open
Abstract
Aims Autologous bone graft (ABG) is considered the 'gold standard' among graft materials for bone regeneration. However, complications including limited availability, donor site morbidity, and deterioration of regenerative capacity over time have been reported. P-15 is a synthetic peptide that mimics the cell binding domain of Type-I collagen. This peptide stimulates new bone formation by enhancing osteogenic cell attachment, proliferation, and differentiation. The objective of this study was to conduct a systematic literature review to determine the clinical efficacy and safety of P-15 peptide in bone regeneration throughout the skeletal system. Methods PubMed, Embase, Web of Science, and Cochrane Library were searched for relevant articles on 13 May 2023. The systematic review was reported according to the PRISMA guidelines. Two reviewers independently screened and assessed the identified articles. Quality assessment was conducted using the methodological index for non-randomized studies and the risk of bias assessment tool for randomized controlled trials. Results After screening, 28 articles were included and grouped by surgical indication, e.g. maxillofacial procedures (n = 18), spine (n = 9), and trauma (n = 1). Published results showed that P-15 peptide was effective in spinal fusion (n = 7) and maxillofacial (n = 11), with very few clinically relevant adverse events related to P-15 peptide. Conclusion This systematic literature review concluded that moderate- (risk of bias, some concern: 50%) to high-quality (risk of bias, low: 46%) clinical evidence exists showing equivalent safety and efficacy in bone regeneration using a P-15 peptide enhanced bone graft substitute compared to ABG. P-15 peptide is safe and effective, resulting in rapid bone formation with a low probability of minor complications.
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Affiliation(s)
- Barend J. Spanninga
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, Maastricht University, Maastricht, Netherlands
| | - Thomáy-Claire A. Hoelen
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, Maastricht University, Maastricht, Netherlands
- Department of Orthopaedic Surgery, CAPHRI research school, Maastricht University Medical Center, Maastricht, Netherlands
| | | | - Boyle Cheng
- Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
- Department of Orthopedic Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
| | - Taco J. Blokhuis
- Department of Orthopaedic Surgery, CAPHRI research school, Maastricht University Medical Center, Maastricht, Netherlands
- Department of Surgery, Maastricht University Medical Centre, NUTRIM research school, Maastricht, Netherlands
| | - Paul C. Willems
- Department of Orthopaedic Surgery, CAPHRI research school, Maastricht University Medical Center, Maastricht, Netherlands
| | - Jacobus J. C. Arts
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, Maastricht University, Maastricht, Netherlands
- Department of Orthopaedic Surgery, CAPHRI research school, Maastricht University Medical Center, Maastricht, Netherlands
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands
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Ramaraju H, Garcia-Gomez E, McAtee AM, Verga AS, Hollister SJ. Shape memory cycle conditions impact human bone marrow stromal cell binding to RGD- and YIGSR-conjugated poly (glycerol dodecanedioate). Acta Biomater 2024; 186:246-259. [PMID: 39111679 DOI: 10.1016/j.actbio.2024.07.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 07/21/2024] [Accepted: 07/30/2024] [Indexed: 08/16/2024]
Abstract
Bioresorbable shape memory polymers (SMP) are an emerging class of polymers that can help address several challenges associated with minimally invasive surgery by providing a solution for structural tissue repair. Like most synthetic polymer networks, SMPs require additional biorelevance and modification for biomedical applications. Methodologies used to incorporate bioactive ligands must preserve SMP thermomechanics and ensure biofunctionality following in vivo delivery. We have previously described the development of a novel thermoresponsive bioresorbable SMP, poly (glycerol dodecanedioate) (PGD). In this study, cell-adhesive peptide sequences RGD and YIGSR were conjugated with PGD. We investigated 1) the impact of conjugated peptides on the fixity (Rf), recovery (Rr), and recovery rate (dRr/dT), 2) the impact of conjugated peptides on cell binding, and 3) the impact of the shape memory cycle (Tprog) on conjugated peptide functionality towards binding human bone marrow stromal cells (BMSC). Peptide conjugation conditions impact fixity but not the recovery or recovery rate (p < 0.01). Peptide-conjugated substrates increased cell attachment and proliferation compared with controls (p < 0.001). Using complementary integrin binding cell-adhesive peptides increased proliferation compared with using single peptides (p < 0.05). Peptides bound to PGD substrates exhibited specificity to their respective integrin targets. Following the shape memory cycle, peptides maintained functionality and specificity depending on the shape memory cycle conditions (p < 0.001). The dissipation of strain energy during recovery can drive differential arrangement of conjugated sequences impacting functionality, an important design consideration for functionalized SMPs. STATEMENT OF SIGNIFICANCE: Shape memory elastomers are an emerging class of polymers that are well-suited for minimally invasive repair of soft tissues. Tissue engineering approaches commonly utilize biodegradable scaffolds to deliver instructive cues, including cells and bioactive signals. Delivering these instructive cues on biodegradable shape memory elastomers requires modification with bioactive ligands. Furthermore, it is necessary to ensure the specificity of the ligands to their biological targets when conjugated to the polymer. Moreover, the bioactive ligand functionality must be conserved after completing the shape memory cycle, for applications in tissue engineering.
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Affiliation(s)
- Harsha Ramaraju
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States.
| | - Elisa Garcia-Gomez
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Annabel M McAtee
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Adam S Verga
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Scott J Hollister
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
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Cheng CT, Vyas PS, McClain EJ, Hoelen TCA, Arts JJC, McLaughlin C, Altman DT, Yu AK, Cheng BC. The Osteogenic Peptide P-15 for Bone Regeneration: A Narrative Review of the Evidence for a Mechanism of Action. Bioengineering (Basel) 2024; 11:599. [PMID: 38927835 PMCID: PMC11200470 DOI: 10.3390/bioengineering11060599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/22/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Bone regeneration is a complex multicellular process involving the recruitment and attachment of osteoprogenitors and their subsequent differentiation into osteoblasts that deposit extracellular matrixes. There is a growing demand for synthetic bone graft materials that can be used to augment these processes to enhance the healing of bone defects resulting from trauma, disease or surgery. P-15 is a small synthetic peptide that is identical in sequence to the cell-binding domain of type I collagen and has been extensively demonstrated in vitro and in vivo to enhance the adhesion, differentiation and proliferation of stem cells involved in bone formation. These events can be categorized into three phases: attachment, activation and amplification. This narrative review summarizes the large body of preclinical research on P-15 in terms of these phases to describe the mechanism of action by which P-15 improves bone formation. Knowledge of this mechanism of action will help to inform the use of P-15 in clinical practice as well as the development of methods of delivering P-15 that optimize clinical outcomes.
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Affiliation(s)
- Cooper T. Cheng
- Neuroscience Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (C.T.C.); (P.S.V.); (C.M.)
| | - Praveer S. Vyas
- Neuroscience Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (C.T.C.); (P.S.V.); (C.M.)
| | - Edward James McClain
- Neuroscience Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (C.T.C.); (P.S.V.); (C.M.)
| | - Thomáy-Claire Ayala Hoelen
- Department of Orthopedic Surgery and CAPHRI Research School, Maastricht University Medical Center (MUMC+), P.O. Box 616 Maastricht, The Netherlands; (T.-C.A.H.); (J.J.C.A.)
| | - Jacobus Johannes Chris Arts
- Department of Orthopedic Surgery and CAPHRI Research School, Maastricht University Medical Center (MUMC+), P.O. Box 616 Maastricht, The Netherlands; (T.-C.A.H.); (J.J.C.A.)
| | - Colin McLaughlin
- Neuroscience Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (C.T.C.); (P.S.V.); (C.M.)
| | - Daniel T. Altman
- Department of Orthopaedic Surgery, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA;
| | - Alexander K. Yu
- Department of Neurosurgery, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA;
| | - Boyle C. Cheng
- Neuroscience Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (C.T.C.); (P.S.V.); (C.M.)
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Inglis JE, Goodwin AM, Divi SN, Hsu WK. Advances in Synthetic Grafts in Spinal Fusion Surgery. Int J Spine Surg 2023; 17:S18-S27. [PMID: 37748919 PMCID: PMC10753330 DOI: 10.14444/8557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023] Open
Abstract
Degenerative spine disease is increasing in prevalence as the global population ages, indicating a need for targeted therapies and continued innovations. While autograft and allograft have historically demonstrated robust results in spine fusion surgery, they have significant limitations and associated complications such as infection, donor site morbidity and pain, and neurovascular injury. Synthetic grafts may provide similar success while mitigating negative outcomes. A narrative literature review was performed to review available synthetic materials that aim to optimize spinal fusion. The authors specifically address the evolution of synthetics and comment on future trends. Novel synthetic materials currently in use include ceramics, synthetic polymers and peptides, bioactive glasses, and peptide amphiphiles, and the authors focus on their success in both human and animal models, physical properties, advantages, and disadvantages. Advantages include properties of osteoinduction, osteoconduction, and osteogenesis, whereas disadvantages encompass a lack of these properties or growth factor-induced complications. Typically, the use of synthetic materials results in fewer complications and lower costs. While the development and tuning of synthetic materials are ongoing, there are many beneficial alternatives to autografts and allografts with promising fusion results.
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Affiliation(s)
- Jacqueline E Inglis
- Department of Orthopedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Alyssa M Goodwin
- Department of Orthopedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Srikanth N Divi
- Department of Orthopedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Wellington K Hsu
- Department of Orthopedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Md Dali SS, Wong SK, Chin KY, Ahmad F. The Osteogenic Properties of Calcium Phosphate Cement Doped with Synthetic Materials: A Structured Narrative Review of Preclinical Evidence. Int J Mol Sci 2023; 24:ijms24087161. [PMID: 37108321 PMCID: PMC10138398 DOI: 10.3390/ijms24087161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/07/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Bone grafting is commonly used as a treatment to repair bone defects. However, its use is challenged by the presence of medical conditions that weaken the bone, like osteoporosis. Calcium phosphate cement (CPC) is used to restore bone defects, and it is commonly available as a bioabsorbable cement paste. However, its use in clinical settings is limited by inadequate mechanical strength, inferior anti-washout characteristics, and poor osteogenic activity. There have been attempts to overcome these shortcomings by adding various natural or synthetic materials as enhancers to CPC. This review summarises the current evidence on the physical, mechanical, and biological properties of CPC after doping with synthetic materials. The incorporation of CPC with polymers, biomimetic materials, chemical elements/compounds, and combination with two or more synthetic materials showed improvement in biocompatibility, bioactivity, anti-washout properties, and mechanical strength. However, the mechanical property of CPC doped with trimethyl chitosan or strontium was decreased. In conclusion, doping of synthetic materials enhances the osteogenic features of pure CPC. The positive findings from in vitro and in vivo studies await further validation on the efficacy of these reinforced CPC composites in clinical settings.
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Affiliation(s)
- Siti Sarah Md Dali
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | - Sok Kuan Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | - Fairus Ahmad
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
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Loenen ACY, Connor J, Johnson S, Davis K, Hannigan N, Barnes T, Arts JJ, van Rietbergen B. Peptide Enhanced Bone Graft Substitute Presents Improved Short-Term Increase in Bone Volume and Construct Stiffness Compared to Iliac Crest Autologous Bone in an Ovine Lumbar Interbody Fusion Model. Global Spine J 2022; 12:1330-1337. [PMID: 33406899 PMCID: PMC9393976 DOI: 10.1177/2192568220979839] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
STUDY DESIGN Preclinical ovine model. OBJECTIVE To assess the in vivo efficacy and safety of the P-15 L bone graft substitute and compare its performance to autologous iliac crest bone graft (ICBG) for lumbar interbody fusion indications. METHODS Thirty skeletally mature sheep underwent lumbar interbody fusion surgery. Half of the sheep received autologous ICBG and the other half the peptide enhanced bone graft substitute (P-15 L). Following termination at 1, 3, and 6 months after surgery, the operated segments were analyzed using micro computed tomography (µCT), histology, and destructive mechanical testing. Additional systemic health monitoring was performed for the P-15 L group. RESULTS One month after surgery, there was only minor evidence of bone remodeling and residual graft material could be clearly observed within the cage. There was active bone remodeling between 1 and 3 months after surgery. At 3 months after surgery significantly denser and stiffer bone was found in the P-15 L group, whereas at 6 months, P-15 L and ICBG gave similar fusion results. The P-15 L bone graft substitute did not have any adverse effects on systemic health. CONCLUSIONS The drug device combination P-15 L was demonstrated to be effective and save for lumbar interbody fusion as evidenced by this ovine model. Compared to autologous ICBG, P-15 L seems to expedite bone formation and remodeling but in the longer-term fusion results were similar.
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Affiliation(s)
- Arjan C. Y. Loenen
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, CAPHRI, Maastricht University Medical Centre, Maastricht, the Netherlands,Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
| | | | | | | | | | | | - Jacobus J. Arts
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, CAPHRI, Maastricht University Medical Centre, Maastricht, the Netherlands,Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Bert van Rietbergen
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, CAPHRI, Maastricht University Medical Centre, Maastricht, the Netherlands,Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands,Bert van Rietbergen, Department of Biomedical Engineering, Eindhoven University of Technology, Buidling 15, Gemini-Zuid (4.118), PO Box 513, 5600 MB Eindhoven, the Netherlands; Groene Loper, TU Eindhoven, De Rondom 70, 5612AP Eindhoven, the Netherlands.
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7
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O’Brien MJM, Jones DM, Semciw AI, Balakumar J, Grabinski R, Roebert J, Coburn GM, Mechlenburg I, Kemp JL. Does the use of i-FACTOR bone graft affect bone healing in those undergoing periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH)? A retrospective study. J Hip Preserv Surg 2022; 9:165-171. [PMID: 37063347 PMCID: PMC10093896 DOI: 10.1093/jhps/hnac027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 03/02/2022] [Accepted: 05/11/2022] [Indexed: 04/18/2023] Open
Abstract
ABSTRACT
The aims of this study were to compare, in patients with and without the use of i-FACTOR bone graft during periacetabular osteotomy (PAO) surgery for developmental dysplasia of the hip (DDH), (i) bone healing at six-weeks post-operatively (ii) rate of complications. This was a retrospective review of case records. Participants were people aged 15-50 years undergoing rectus-sparing minimally invasive PAO surgery for DDH. Group 1: patients with i-FACTOR, Group 2: No i-FACTOR. The primary outcome was the rate of bone healing on radiographs at 6 weeks. The likelihood of bone healing was compared using logistic regression with Generalised Estimating Equations (GEE) and expressed as odds ratios (95% confidence intervals (CIs; P < 0.05)). The occurrence of complications was extracted from surgical records. The i-FACTOR group had 3-times greater odds of partial/full union than those without [adjusted odds ratio (95% CIs, P-value)]: [3.265 (1.032 to 10.330, P = 0.044)]. The i-FACTOR group had 89% partial/full union at 6-weeks, compared to 69% of the non-i-FACTOR group. Half of the patients had leaking of bone graft in the i-FACTOR group versus 10% in the non-i-FACTOR group, 26% of the i-FACTOR group and 12% of the non-i-FACTOR group had neuropraxia of the lateral femoral cutaneous nerve (LFCN). Complication rates were low, and similar between groups. However, the rate of LFCN neuropraxia and bone graft leakage was higher in the i-FACTOR. These findings should be confirmed in a future prospective randomised clinical trial and include outcomes such as pain and quality of life.
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Affiliation(s)
| | | | - Adam Ivan Semciw
- Department of Physiotherapy, Podiatry, and
Prosthetics and Orthotics, La Trobe University, Melbourne, VIC 3086,
Australia
| | | | - Rafal Grabinski
- Victoria House Imaging, I-Med
Radiology, Melbourne, VIC 3141, Australia
| | - Justin Roebert
- Victoria House Imaging, I-Med
Radiology, Melbourne, VIC 3141, Australia
| | - Georgia M Coburn
- La Trobe Sport and Exercise Medicine Research
Centre, La Trobe University, Melbourne, VIC 3086, Australia
| | - Inger Mechlenburg
- Department of Orthopaedics, Aarhus University
Hospital, Aarhus 8200, Denmark
- Department of Clinical Medicine, Aarhus
University, Aarhus 8200, Denmark
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Erickson CB, Hill R, Pascablo D, Kazakia G, Hansen K, Bahney C. A timeseries analysis of the fracture callus extracellular matrix proteome during bone fracture healing. JOURNAL OF LIFE SCIENCES (WESTLAKE VILLAGE, CALIF.) 2021; 3:1-30. [PMID: 35765657 PMCID: PMC9236279 DOI: 10.36069/jols/20220601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
While most bones fully self-heal, certain diseases require bone allograft to assist with fracture healing. Bone allografts offer promise as treatments for such fractures due to their osteogenic properties. However, current bone allografts made of decellularized bone extracellular matrix (ECM) have high failure rates, and thus grafts which improve fracture healing outcomes are needed. Understanding specific changes to the ECM proteome during normal fracture healing would enable the identification of key proteins that could be used enhance osteogenicity of bone allograft. Here, we performed a timeseries analysis of the fracture callus in mice to investigate proteomic and mineralization changes to the ECM at key stages of fracture healing. We found that changes to the ECM proteome largely coincide with the distinct phases of fracture healing. Basement membrane proteins (AGRN, COL4, LAMA), cartilage proteins (COL2A1, ACAN), and collagen crosslinking enzymes (LOXL, PLOD, ITIH) were initially upregulated, followed by bone specific proteoglycans and collagens (IBSP, COL1A1). Various tissue proteases (MMP2, 9, 13, 14; CTSK, CTSG, ELANE) were expressed at different levels throughout fracture healing. These changes coordinated with mineralization of the fracture callus, which increased steeply during the initial stages of healing. Interestingly the later timepoint was characterized by a response to wound healing and high expression of clotting factors (F2, 7, 9, 10). We identified ELANE and ITIH2 as tissue remodeling enzymes having no prior known involvement with fracture healing. This data can be further mined to identify regenerative proteins for enhanced bone graft design.
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Affiliation(s)
- Christopher B. Erickson
- Department of Biochemistry and Molecular Genetics,University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Ryan Hill
- Department of Biochemistry and Molecular Genetics,University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Donna Pascablo
- Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA
| | - Galateia Kazakia
- Department of Radiology and Biomedical Imaging, University of California, San Francisco (UCSF), San Francisco, CA
| | - Kirk Hansen
- Department of Biochemistry and Molecular Genetics,University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Chelsea Bahney
- Stedman Philippon Research Institute (SPRI), Center for Regenerative and Personalized Medicine. Vail, CO
- Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA
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Krenzlin H, Foelger A, Mailänder V, Blase C, Brockmann M, Düber C, Ringel F, Keric N. Novel Biodegradable Composite of Calcium Phosphate Cement and the Collagen I Mimetic P-15 for Pedicle Screw Augmentation in Osteoporotic Bone. Biomedicines 2021; 9:biomedicines9101392. [PMID: 34680509 PMCID: PMC8533375 DOI: 10.3390/biomedicines9101392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 11/26/2022] Open
Abstract
Osteoporotic vertebral fractures often necessitate fusion surgery, with high rates of implant failure. We present a novel bioactive composite of calcium phosphate cement (CPC) and the collagen I mimetic P-15 for pedicle screw augmentation in osteoporotic bone. Methods involved expression analysis of osteogenesis-related genes during osteoblastic differentiation by RT-PCR and immunostaining of osteopontin and Ca2+ deposits. Untreated and decalcified sheep vertebrae were utilized for linear pullout testing of pedicle screws. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA). Expression of ALPI II (p < 0.0001), osteopontin (p < 0.0001), RUNX2 (p < 0.0001), and osteocalcin (p < 0.0001) was upregulated after co-culture of MSC with CPC-P-15. BMD was decreased by 28.75% ± 2.6%. Pullout loads in untreated vertebrae were 1405 ± 6 N (p < 0.001) without augmentation, 2010 ± 168 N (p < 0.0001) after augmentation with CPC-P-15, and 2112 ± 98 N (p < 0.0001) with PMMA. In decalcified vertebrae, pullout loads were 828 ± 66 N (p < 0.0001) without augmentation, 1324 ± 712 N (p = 0.04) with PMMA, and 1252 ± 131 N (p < 0.0078) with CPC-P-15. CPC-P-15 induces osteoblastic differentiation of human MES and improves pullout resistance of pedicle screws in osteoporotic and non-osteoporotic bone.
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Affiliation(s)
- Harald Krenzlin
- Department of Neurosurgery, University Medical Center Mainz, 55131 Mainz, Germany; (A.F.); (F.R.); (N.K.)
- Correspondence:
| | - Andrea Foelger
- Department of Neurosurgery, University Medical Center Mainz, 55131 Mainz, Germany; (A.F.); (F.R.); (N.K.)
| | - Volker Mailänder
- Max Planck Institute for Polymer Research, 55128 Mainz, Germany;
- Center for Translational Nanomedicine, University Medical Center Mainz, 55131 Maniz, Germany
| | - Christopher Blase
- Personalized Biomedical Engineering Lab, Frankfurt University of Applied Sciences, 60318 Frankfurt am Main, Germany;
| | - Marc Brockmann
- Department of Neuroradiology, University Medical Center Mainz, 55131 Mainz, Germany;
| | - Christoph Düber
- Department of Radiology, University Medical Center Mainz, 55131 Mainz, Germany;
| | - Florian Ringel
- Department of Neurosurgery, University Medical Center Mainz, 55131 Mainz, Germany; (A.F.); (F.R.); (N.K.)
| | - Naureen Keric
- Department of Neurosurgery, University Medical Center Mainz, 55131 Mainz, Germany; (A.F.); (F.R.); (N.K.)
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Commercial Bone Grafts Claimed as an Alternative to Autografts: Current Trends for Clinical Applications in Orthopaedics. MATERIALS 2021; 14:ma14123290. [PMID: 34198691 PMCID: PMC8232314 DOI: 10.3390/ma14123290] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/09/2021] [Accepted: 06/11/2021] [Indexed: 02/08/2023]
Abstract
In the last twenty years, due to an increasing medical and market demand for orthopaedic implants, several grafting options have been developed. However, when alternative bone augmentation materials mimicking autografts are searched on the market, commercially available products may be grouped into three main categories: cellular bone matrices, growth factor enhanced bone grafts, and peptide enhanced xeno-hybrid bone grafts. Firstly, to obtain data for this review, the search engines Google and Bing were employed to acquire information from reports or website portfolios of important competitors in the global bone graft market. Secondly, bibliographic databases such as Medline/PubMed, Web of Science, and Scopus were also employed to analyse data from preclinical/clinical studies performed to evaluate the safety and efficacy of each product released on the market. Here, we discuss several products in terms of osteogenic/osteoinductive/osteoconductive properties, safety, efficacy, and side effects, as well as regulatory issues and costs. Although both positive and negative results were reported in clinical applications for each class of products, to date, peptide enhanced xeno-hybrid bone grafts may represent the best choice in terms of risk/benefit ratio. Nevertheless, more prospective and controlled studies are needed before approval for routine clinical use.
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11
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Bullock G, Atkinson J, Gentile P, Hatton P, Miller C. Osteogenic Peptides and Attachment Methods Determine Tissue Regeneration in Modified Bone Graft Substitutes. J Funct Biomater 2021; 12:22. [PMID: 33807267 PMCID: PMC8103284 DOI: 10.3390/jfb12020022] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/18/2021] [Accepted: 03/24/2021] [Indexed: 01/01/2023] Open
Abstract
The inclusion of biofunctional molecules with synthetic bone graft substitutes has the potential to enhance tissue regeneration during treatment of traumatic bone injuries. The clinical use of growth factors has though been associated with complications, some serious. The use of smaller, active peptides has the potential to overcome these problems and provide a cost-effective, safe route for the manufacture of enhanced bone graft substitutes. This review considers the design of peptide-enhanced bone graft substitutes, and how peptide selection and attachment method determine clinical efficacy. It was determined that covalent attachment may reduce the known risks associated with growth factor-loaded bone graft substitutes, providing a predictable tissue response and greater clinical efficacy. Peptide choice was found to be critical, but even within recognised families of biologically active peptides, the configurations that appeared to most closely mimic the biological molecules involved in natural bone healing processes were most potent. It was concluded that rational, evidence-based design of peptide-enhanced bone graft substitutes offers a pathway to clinical maturity in this highly promising field.
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Affiliation(s)
- George Bullock
- School of Clinical Dentistry, The University of Sheffield, Sheffield S10 2TA, UK; (G.B.); (J.A.); (C.M.)
| | - Joss Atkinson
- School of Clinical Dentistry, The University of Sheffield, Sheffield S10 2TA, UK; (G.B.); (J.A.); (C.M.)
| | - Piergiorgio Gentile
- School of Engineering, Newcastle University, Stephenson Building, Newcastle upon Tyne NE1 7RU, UK;
| | - Paul Hatton
- School of Clinical Dentistry, The University of Sheffield, Sheffield S10 2TA, UK; (G.B.); (J.A.); (C.M.)
| | - Cheryl Miller
- School of Clinical Dentistry, The University of Sheffield, Sheffield S10 2TA, UK; (G.B.); (J.A.); (C.M.)
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Fu L, Omi M, Sun M, Cheng B, Mao G, Liu T, Mendonça G, Averick SE, Mishina Y, Matyjaszewski K. Covalent Attachment of P15 Peptide to Ti Alloy Surface Modified with Polymer to Enhance Osseointegration of Implants. ACS APPLIED MATERIALS & INTERFACES 2019; 11:38531-38536. [PMID: 31599570 PMCID: PMC6993989 DOI: 10.1021/acsami.9b14651] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Titanium (Ti) and its alloys are used in orthopedic and dental implants due to their excellent physical properties and biocompatibility. Although Ti exhibits superior osteoconductive properties compared to those of polymer-based implants, improved bone-on growth properties are required for enhanced surgical outcomes and improved recovery surgical interventions. Herein, we demonstrate a novel surface modification strategy to enhance the osteoconductivity of Ti surfaces through the grafting-from procedure of a reactive copolymer via surface-initiated atom transfer radical polymerization (SI-ATRP). Then, postpolymerization conjugation of the P15 peptide, an osteoblast binding motif, was successfully carried out. Subsequent in vitro studies revealed that the surface modification promoted osteoblast attachment on the Ti discs at 6 and 24 h. Moreover, mineral matrix deposition by osteoblasts was greater for the surface-modified Ti than for plain Ti and P15 randomly absorbed onto the Ti surface. These results suggest that the strategy for postpolymerization incorporation of P15 onto a Ti surface with a polymer interface may provide improved osseointegration outcomes, leading to enhanced quality of life for patients.
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Affiliation(s)
- Liye Fu
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
| | - Maiko Omi
- Department of Biologic and Materials Sciences & Prothodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, United States
| | - Mingkang Sun
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
| | - Boyle Cheng
- Neuroscience Disruptive Research Lab, Allegheny Health Network, 320 East North Avenue, Pittsburgh, Pennsylvania 15212, United States
| | - Gordon Mao
- Neuroscience Disruptive Research Lab, Allegheny Health Network, 320 East North Avenue, Pittsburgh, Pennsylvania 15212, United States
| | - Tong Liu
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
| | - Gustavo Mendonça
- Department of Biologic and Materials Sciences & Prothodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, United States
| | - Saadyah E. Averick
- Neuroscience Disruptive Research Lab, Allegheny Health Network, 320 East North Avenue, Pittsburgh, Pennsylvania 15212, United States
| | - Yuji Mishina
- Department of Biologic and Materials Sciences & Prothodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, United States
| | - Krzysztof Matyjaszewski
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
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13
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Ramaraju H, Kohn DH. Cell and Material-Specific Phage Display Peptides Increase iPS-MSC Mediated Bone and Vasculature Formation In Vivo. Adv Healthc Mater 2019; 8:e1801356. [PMID: 30835955 DOI: 10.1002/adhm.201801356] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 02/04/2019] [Indexed: 01/27/2023]
Abstract
Biomimetically designed materials matching the chemical and mechanical properties of tissue support higher mesenchymal stem cell (MSC) adhesion. However, directing cell-specific attachment and ensuring uniform cell distribution within the interior of 3D biomaterials remain key challenges in healing critical sized defects. Previously, a phage display derived MSC-specific peptide (DPIYALSWSGMA, DPI) was combined with a mineral binding sequence (VTKHLNQISQSY, VTK) to increase the magnitude and specificity of MSC attachment to calcium-phosphate biomaterials in 2D. This study investigates how DPI-VTK influences quantity and uniformity of iPS-MSC mediated bone and vasculature formation in vivo. There is greater bone formation in vivo when iPS-MSCs are transplanted on bone-like mineral (BLM) constructs coated with DPI-VTK compared to VTK (p < 0.002), uncoated BLM (p < 0.037), acellular BLM/DPI-VTK (p < 0.003), and acellular BLM controls (p < 0.01). This study demonstrates, for the first time, the ability of non-native phage-display designed peptides to spatially control uniform cell distribution on 3D scaffolds and increase the magnitude and uniformity of bone and vasculature formation in vivo. Taken together, the study validates phage display as a novel technology platform to engineer non-native peptides with the ability to drive cell specific attachment on biomaterials, direct bone regeneration, and engineer uniform vasculature in vivo.
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Affiliation(s)
- Harsha Ramaraju
- Department of Biologic and Material SciencesDepartment of Biomedical EngineeringUniversity of Michigan 1011 N. University Ave, Room 2213 Ann Arbor MI 48109‐1078 USA
| | - David H. Kohn
- Department of Biologic and Material SciencesDepartment of Biomedical EngineeringUniversity of Michigan 1011 N. University Ave, Room 2213 Ann Arbor MI 48109‐1078 USA
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14
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Sivaraman K, Shanthi C. Matrikines for therapeutic and biomedical applications. Life Sci 2018; 214:22-33. [PMID: 30449450 DOI: 10.1016/j.lfs.2018.10.056] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/24/2018] [Accepted: 10/25/2018] [Indexed: 12/25/2022]
Abstract
Matrikines, peptides originating from the fragmentation of extracellular matrix proteins are identified to play important role in both health and disease. They possess biological activities, much different from their parent protein. Identification of such bioactive cryptic regions in the extracellular matrix proteins has attracted the researchers all over the world in the recent decade. These bioactive peptides could find use in preparation of biomaterials and tissue engineering applications. Matrikines identified in major extracellular matrix (ECM) proteins like collagen, elastin, fibronectin, and laminin are being extensively studied for use in tissue engineering and regenerative medicine. They are identified to modulate cellular activity like cell growth, proliferation, migration and may induce apoptosis. RGD, a well-known peptide identified in fibronectin with cell adhesive property is being investigated in designing biomaterials. Collagen hexapeptide GFOGER was found to promote cell adhesion and differentiation. Laminin also possesses regions with strong cell adhesion property. Recently, cell-penetrating peptides from elastin are used as a targeted delivery system for therapeutic drugs. The continued search for cryptic sequences in the extracellular matrix proteins along with advanced peptide coupling chemistries would lead to biomaterials with improved surface properties. This review article outlines the peptides derived from extracellular matrix and some of the possible applications of these peptides in therapeutics and tissue engineering applications.
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Affiliation(s)
- K Sivaraman
- School of Biosciences and Technology, VIT, Vellore 632014, Tamilnadu, India
| | - C Shanthi
- School of Biosciences and Technology, VIT, Vellore 632014, Tamilnadu, India.
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15
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Ho-Shui-Ling A, Bolander J, Rustom LE, Johnson AW, Luyten FP, Picart C. Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives. Biomaterials 2018; 180:143-162. [PMID: 30036727 PMCID: PMC6710094 DOI: 10.1016/j.biomaterials.2018.07.017] [Citation(s) in RCA: 565] [Impact Index Per Article: 80.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 07/06/2018] [Accepted: 07/10/2018] [Indexed: 12/25/2022]
Abstract
Bone fractures are the most common traumatic injuries in humans. The repair of bone fractures is a regenerative process that recapitulates many of the biological events of embryonic skeletal development. Most of the time it leads to successful healing and the recovery of the damaged bone. Unfortunately, about 5-10% of fractures will lead to delayed healing or non-union, more so in the case of co-morbidities such as diabetes. In this article, we review the different strategies to heal bone defects using synthetic bone graft substitutes, biologically active substances and stem cells. The majority of currently available reviews focus on strategies that are still at the early stages of development and use mostly in vitro experiments with cell lines or stem cells. Here, we focus on what is already implemented in the clinics, what is currently in clinical trials, and what has been tested in animal models. Treatment approaches can be classified in three major categories: i) synthetic bone graft substitutes (BGS) whose architecture and surface can be optimized; ii) BGS combined with bioactive molecules such as growth factors, peptides or small molecules targeting bone precursor cells, bone formation and metabolism; iii) cell-based strategies with progenitor cells combined or not with active molecules that can be injected or seeded on BGS for improved delivery. We review the major types of adult stromal cells (bone marrow, adipose and periosteum derived) that have been used and compare their properties. Finally, we discuss the remaining challenges that need to be addressed to significantly improve the healing of bone defects.
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Affiliation(s)
- Antalya Ho-Shui-Ling
- Grenoble Institute of Technology, Univ. Grenoble Alpes, 38000 Grenoble, France; CNRS, LMGP, 3 Parvis Louis Néel, 38031 Grenoble Cedex 01, France
| | - Johanna Bolander
- Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center, KU Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Belgium
| | - Laurence E Rustom
- Department of Bioengineering, University of Illinois at Urbana-Champaign, 1304 West Springfield Avenue, Urbana, IL 61801, USA
| | - Amy Wagoner Johnson
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, 1206 West Green Street, Urbana, IL 61081, USA; Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, IL 61801, USA
| | - Frank P Luyten
- Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center, KU Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Belgium.
| | - Catherine Picart
- Grenoble Institute of Technology, Univ. Grenoble Alpes, 38000 Grenoble, France; CNRS, LMGP, 3 Parvis Louis Néel, 38031 Grenoble Cedex 01, France.
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16
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Oxborrow N, Sundarapandian R. Heterotopic ossification following use of i-Factor for spinal fusion in Mucopolysaccharidosis 1: a case report. J Surg Case Rep 2018; 2018:rjy120. [PMID: 29977512 PMCID: PMC6007486 DOI: 10.1093/jscr/rjy120] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 05/30/2018] [Indexed: 11/13/2022] Open
Abstract
Mucopolysaccharidosis is a rare group of genetic disorder which results in a complex of anomalies involving various systems. In Mucopolysaccharidosis 1 progressive thoracolumbar kyphosis is a common presentation which can result in instability and neurological deficit. Posterior spinal surgery is performed to correct deformity and obtain spinal fusion. Peptide enhanced bone graft substitute (i-FactorTM) is relatively a new component with proven efficacy to obtain early spinal fusion. An 8-year-old child with progressive high lumbar kyphosis due to Mucopolysaccharidosis 1 was admitted for Posterior spinal fusion with i-Factor bone graft substitute. Postoperatively patient had serous discharge from the wound which settled without intervention. A month after the surgery spinal radiographs revealed heterotopic ossification at the distal end of spinal construct in the paraspinal region. Patient remained asymptomatic and clinically well.
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Affiliation(s)
- Neil Oxborrow
- Royal Manchester Children's Hospital, Oxford Road, Manchester, UK
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17
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Toosi S, Behravan N, Behravan J. Nonunion fractures, mesenchymal stem cells and bone tissue engineering. J Biomed Mater Res A 2018; 106:2552-2562. [PMID: 29689623 DOI: 10.1002/jbm.a.36433] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 03/22/2018] [Accepted: 04/10/2018] [Indexed: 12/15/2022]
Abstract
Depending on the duration of healing process, 5-10% of bone fractures may result in either nonunion or delayed union. Because nonunions remain a clinically important problem, there is interest in the utilization of tissue engineering strategies to augment bone fracture repair. Three basic biologic elements that are required for bone regeneration include cells, extracellular matrix scaffolds and biological adjuvants for growth, differentiation and angiogenesis. Mesenchymal stem cells (MSCs) are capable to differentiate into various types of the cells including chondrocytes, myoblasts, osteoblasts, and adipocytes. Due to their potential for multilineage differentiation, MSCs are considered important contributors in bone tissue engineering research. In this review we highlight the progress in the application of biomaterials, stem cells and tissue engineering in promoting nonunion bone fracture healing. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2551-2561, 2018.
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Affiliation(s)
- Shirin Toosi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Behravan
- Exceptionally Talented Students Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Behravan
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Ramaraju H, Miller SJ, Kohn DH. Dual-functioning peptides discovered by phage display increase the magnitude and specificity of BMSC attachment to mineralized biomaterials. Biomaterials 2017; 134:1-12. [PMID: 28453953 DOI: 10.1016/j.biomaterials.2017.04.034] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 04/17/2017] [Indexed: 02/09/2023]
Abstract
Design of biomaterials for cell-based therapies requires presentation of specific physical and chemical cues to cells, analogous to cues provided by native extracellular matrices (ECM). We previously identified a peptide sequence with high affinity towards apatite (VTKHLNQISQSY, VTK) using phage display. The aims of this study were to identify a human MSC-specific peptide sequence through phage display, combine it with the apatite-specific sequence, and verify the specificity of the combined dual-functioning peptide to both apatite and human bone marrow stromal cells. In this study, a combinatorial phage display identified the cell binding sequence (DPIYALSWSGMA, DPI) which was combined with the mineral binding sequence to generate the dual peptide DPI-VTK. DPI-VTK demonstrated significantly greater binding affinity (1/KD) to apatite surfaces compared to VTK, phosphorylated VTK (VTKphos), DPI-VTKphos, RGD-VTK, and peptide-free apatite surfaces (p < 0.01), while significantly increasing hBMSC adhesion strength (τ50, p < 0.01). MSCs demonstrated significantly greater adhesion strength to DPI-VTK compared to other cell types, while attachment of MC3T3 pre-osteoblasts and murine fibroblasts was limited (p < 0.01). MSCs on DPI-VTK coated surfaces also demonstrated increased spreading compared to pre-osteoblasts and fibroblasts. MSCs cultured on DPI-VTK coated apatite films exhibited significantly greater proliferation compared to controls (p < 0.001). Moreover, early and late stage osteogenic differentiation markers were elevated on DPI-VTK coated apatite films compared to controls. Taken together, phage display can identify non-obvious cell and material specific peptides to increase human MSC adhesion strength to specific biomaterial surfaces and subsequently increase cell proliferation and differentiation. These new peptides expand biomaterial design methodology for cell-based regeneration of bone defects. This strategy of combining cell and material binding phage display derived peptides is broadly applicable to a variety of systems requiring targeted adhesion of specific cell populations, and may be generalized to the engineering of any adhesion surface.
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Affiliation(s)
- Harsha Ramaraju
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Sharon J Miller
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - David H Kohn
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Biologic and Material Sciences, University of Michigan, Ann Arbor, MI, USA.
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19
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Zhang J, Eisenhauer P, Kaya O, Vaccaro AR, Diallo C, Fertala A, Freeman TA. P15 peptide stimulates chondrogenic commitment and endochondral ossification. INTERNATIONAL ORTHOPAEDICS 2017; 41:1413-1422. [DOI: 10.1007/s00264-017-3464-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 03/22/2017] [Indexed: 12/01/2022]
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20
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Visser R, Rico-Llanos GA, Pulkkinen H, Becerra J. Peptides for bone tissue engineering. J Control Release 2016; 244:122-135. [PMID: 27794492 DOI: 10.1016/j.jconrel.2016.10.024] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/21/2016] [Accepted: 10/23/2016] [Indexed: 01/07/2023]
Abstract
Molecular signals in the form of growth factors are the main modulators of cell behavior. However, the use of growth factors in tissue engineering has several drawbacks, including their costs, difficult production, immunogenicity and short half-life. Furthermore, many of them are pleiotropic and, since a single growth factor can have different active domains, their effect is not always fully controllable. A very interesting alternative that has recently emerged is the use of biomimetic peptides. Sequences derived from the active domains of soluble or extracellular matrix proteins can be used to functionalize the biomaterials used as scaffolds for new tissue growth to either direct the attachment of cells or to be released as soluble ligands. Since these short peptides can be easily designed and cost-effectively synthesized in vitro, their use has opened up a world of new opportunities to obtain cheaper and more effective implants for regenerative medicine strategies. In this extensive review we will go through many of the most important peptides with potential interest for bone tissue engineering, not limiting to those that only mediate cell adhesion or induce the osteogenic differentiation of progenitor cells, but also focusing on those that direct angiogenesis because of its close relation with bone formation.
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Affiliation(s)
- Rick Visser
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), Malaga, Spain; Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Spain; BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain.
| | - Gustavo A Rico-Llanos
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), Malaga, Spain; Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Spain; BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain
| | - Hertta Pulkkinen
- BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Jose Becerra
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), Malaga, Spain; Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Spain; BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain
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21
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Pountos I, Panteli M, Lampropoulos A, Jones E, Calori GM, Giannoudis PV. The role of peptides in bone healing and regeneration: a systematic review. BMC Med 2016; 14:103. [PMID: 27400961 PMCID: PMC4940902 DOI: 10.1186/s12916-016-0646-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Bone tissue engineering and the research surrounding peptides has expanded significantly over the last few decades. Several peptides have been shown to support and stimulate the bone healing response and have been proposed as therapeutic vehicles for clinical use. The aim of this comprehensive review is to present the clinical and experimental studies analysing the potential role of peptides for bone healing and bone regeneration. METHODS A systematic review according to PRISMA guidelines was conducted. Articles presenting peptides capable of exerting an upregulatory effect on osteoprogenitor cells and bone healing were included in the study. RESULTS Based on the available literature, a significant amount of experimental in vitro and in vivo evidence exists. Several peptides were found to upregulate the bone healing response in experimental models and could act as potential candidates for future clinical applications. However, from the available peptides that reached the level of clinical trials, the presented results are limited. CONCLUSION Further research is desirable to shed more light into the processes governing the osteoprogenitor cellular responses. With further advances in the field of biomimetic materials and scaffolds, new treatment modalities for bone repair will emerge.
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Affiliation(s)
- Ippokratis Pountos
- Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds, UK
| | - Michalis Panteli
- Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds, UK
| | | | - Elena Jones
- Unit of Musculoskeletal Disease, Leeds Institute of Rheumatic and Musculoskeletal Medicine, St. James University Hospital, University of Leeds, LS9 7TF, Leeds, UK
| | - Giorgio Maria Calori
- Department of Trauma & Orthopaedics, School of Medicine, ISTITUTO ORTOPEDICO GAETANO PINI, Milan, Italy
| | - Peter V Giannoudis
- Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds, UK. .,NIHR Leeds Biomedical Research Unit, Chapel Allerton Hospital, LS7 4SA Leeds, West Yorkshire, Leeds, UK.
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22
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Efficacy of i-Factor Bone Graft versus Autograft in Anterior Cervical Discectomy and Fusion: Results of the Prospective, Randomized, Single-blinded Food and Drug Administration Investigational Device Exemption Study. Spine (Phila Pa 1976) 2016; 41:1075-1083. [PMID: 26825787 DOI: 10.1097/brs.0000000000001466] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A prospective, randomized, controlled, parallel, single-blinded noninferiority multicenter pivotal FDA IDE trial. OBJECTIVE The objective of this study was to investigate efficacy and safety of i-Factor Bone Graft (i-Factor) compared with local autograft in single-level anterior cervical discectomy and fusion (ACDF) for cervical radiculopathy. SUMMARY OF BACKGROUND DATA i-Factor is a composite bone substitute material consisting of the P-15 synthetic collagen fragment adsorbed onto anorganic bone mineral and suspended in an inert biocompatible hydrogel carrier. P-15 has demonstrated bone healing efficacy in dental, orthopedic, and nonhuman applications. METHODS Patients randomly received either autograft (N = 154) or i-Factor (N = 165) in a cortical ring allograft. Study success was defined as noninferiority in fusion, Neck Disability Index (NDI), and Neurological Success endpoints, and similar adverse events profile at 12 months. RESULTS At 12 months (follow-up rate 87%), both i-Factor and autograft subjects demonstrated a high fusion rate (88.97% and 85.82%, respectively, noninferiority P = 0.0004), significant improvements in NDI (28.75 and 27.40, respectively, noninferiority P < 0.0001), and high Neurological Success rate (93.71% and 93.01%, respectively, noninferiority P < 0.0001). There was no difference in the rate of adverse events (83.64% and 82.47% in the i-Factor and autograft groups, respectively, P = 0.8814). Overall success rate consisting of fusion, NDI, Neurological Success and Safety Success was higher in i-Factor subjects than in autograft subjects (68.75% and 56.94%, respectively, P = 0.0382). Improvements in VAS pain and SF-36v2 scores were clinically relevant and similar between the groups. A high proportion of patients reported good or excellent Odom outcomes (81.4% in both groups). CONCLUSION i-Factor has met all four FDA mandated noninferiority success criteria and has demonstrated safety and efficacy in single-level ACDF for cervical radiculopathy. i-Factor and autograft groups demonstrated significant postsurgical improvement and high fusion rates. LEVEL OF EVIDENCE 1.
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23
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Amso Z, Cornish J, Brimble MA. Short Anabolic Peptides for Bone Growth. Med Res Rev 2016; 36:579-640. [DOI: 10.1002/med.21388] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/24/2016] [Accepted: 02/15/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Zaid Amso
- School of Chemical Sciences; The University of Auckland, 23 Symonds St; Auckland 1142 New Zealand
| | - Jillian Cornish
- Department of Medicine; The University of Auckland; Auckland 1010 New Zealand
| | - Margaret A. Brimble
- School of Chemical Sciences; The University of Auckland, 23 Symonds St; Auckland 1142 New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences; The University of Auckland; Auckland 1142 New Zealand
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Shankar SP, Griffith M, Forrester JV, Kuffová L. Dendritic cells and the extracellular matrix: A challenge for maintaining tolerance/homeostasis. World J Immunol 2015; 5:113-130. [DOI: 10.5411/wji.v5.i3.113] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 09/18/2015] [Accepted: 11/11/2015] [Indexed: 02/05/2023] Open
Abstract
The importance of the extracellular matrix (ECM) in contributing to structural, mechanical, functional and tissue-specific features in the body is well appreciated. While the ECM was previously considered to be a passive bystander, it is now evident that it plays active, dynamic and flexible roles in shaping cell survival, differentiation, migration and death to varying extents depending on the specific site in the body. Dendritic cells (DCs) are recognized as potent antigen presenting cells present in many tissues and in blood, continuously scrutinizing the microenvironment for antigens and mounting local and systemic host responses against harmful agents. DCs also play pivotal roles in maintaining homeostasis to harmless self-antigens, critical for preventing autoimmunity. What is less understood are the complex interactions between DCs and the ECM in maintaining this balance between steady-state tissue residence and DC activation during inflammation. DCs are finely tuned to inflammation-induced variations in fragment length, accessible epitopes and post-translational modifications of individual ECM components and correspondingly interpret these changes appropriately by adjusting their profiles of cognate binding receptors and downstream immune activation. The successful design and composition of novel ECM-based mimetics in regenerative medicine and other applications rely on our improved understanding of DC-ECM interplay in homeostasis and the challenges involved in maintaining it.
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Effects of P-15 Peptide Coated Hydroxyapatite on Tibial Defect Repair In Vivo in Normal and Osteoporotic Rats. BIOMED RESEARCH INTERNATIONAL 2015; 2015:253858. [PMID: 26509146 PMCID: PMC4609767 DOI: 10.1155/2015/253858] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 07/29/2015] [Indexed: 11/30/2022]
Abstract
This study assessed the efficacy of anorganic bone mineral coated with P-15 peptide (ABM/P-15) on tibia defect repair longitudinally in both normal and osteoporotic rats in vivo. A paired design was used. 24 Norwegian brown rats were divided into normal and osteoporotic groups. 48 cylindrical defects were created in proximal tibias bilaterally. Defects were filled with ABM/P-15 or left empty. Osteoporotic status was assessed by microarchitectural analysis. Microarchitectural properties of proximal tibial defects were evaluated at 4 time points. 21 days after surgery, tibias were harvested for histology and histomorphometry. Significantly increased bone volume fraction, surface density, and connectivity were seen in all groups at days 14 and 21 compared with day 0. Moreover, the structure type of ABM/P-15 group was changed toward typical plate-like structure. Microarchitectural properties of ABM/P-15 treated newly formed bones at 21 days were similar in normal and osteoporotic rats. Histologically, significant bone formation was seen in all groups. Interestingly, significantly increased bone formation was seen in osteoporotic rats treated with ABM/P-15 indicating optimized healing potential. Empty defects showed lower healing potential in osteoporotic bone. In conclusion, ABM/P-15 accelerated bone regeneration in osteoporotic rats but did not enhance bone regeneration in normal rats.
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Lauweryns P, Raskin Y. Prospective analysis of a new bone graft in lumbar interbody fusion: results of a 2- year prospective clinical and radiological study. Int J Spine Surg 2015; 9:14444-2002. [PMID: 25709887 PMCID: PMC4337192 DOI: 10.14444/2002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Background This study examined the efficacy and safety of bone graft material ABM/P-15 (iFACTOR) for use in posterior lumbar interbody fusion. ABM/P-15 has been used safely for more than a decade in dental applications. Methods Forty patients underwent PLIF surgery, with each patient as control. Assessments up to 24 months included radiographs, CT scan, VAS, and ODI. Primary success criteria were fusion and safety. Results Intra-cage bridging bone occurred earlier with ABM/P-15 than autograft (97.73% vs. 59.09% at 6 months). On average pain decreased 29 points and function improved 43 points. Radio dense material outside the disk space occurred more frequently with ABM/P-15 than autograft, without clinical consequence. Conclusions This study suggests that ABM/P-15 has equal or greater efficacy at 6 and 12 months. Pain improvements exceeded success criteria at all time points. Functional improvement exceeded success criteria at all time points. Clinical Relevance This study explores the safety and efficacy of an osteobiologic peptide enhanced bone graft material as a viable alternative to autograft and its attendant risks.
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Affiliation(s)
| | - Yannic Raskin
- Orthopaedic Surgery, Sint-Trudo ZiekenHuis, Sint- Truiden, Belgium
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Mobbs RJ, Maharaj M, Rao PJ. Clinical outcomes and fusion rates following anterior lumbar interbody fusion with bone graft substitute i-FACTOR, an anorganic bone matrix/P-15 composite. J Neurosurg Spine 2014; 21:867-76. [DOI: 10.3171/2014.9.spine131151] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Despite limited availability and the morbidity associated with autologous iliac crest bone graft (ICBG), its use in anterior lumbar interbody fusion (ALIF) procedures remains the gold standard to achieve arthrodesis. The search for alternative grafts yielding comparable or superior fusion outcomes with fewer complications continues. In particular, i-FACTOR, a novel bone graft substitute composed of anorganic bone matrix (ABM) with P-15 small peptide, is one example currently used widely in the dental community. Although preclinical studies have documented its usefulness, the role of i-FACTOR in ALIF procedures remains unknown.
The authors' goal was to determine the safety and efficacy of i-FACTOR bone graft composite used in patients who underwent ALIF by evaluating fusion rates and clinical outcomes.
Methods
A nonblinded cohort of patients who were all referred to a single surgeon's practice was prospectively studied. One hundred ten patients with degenerative spinal disease underwent single or multilevel ALIF using the ABM/P-15 bone graft composite with a mean of 24 months (minimum 15 months) of follow-up were enrolled in the study. Patient's clinical outcomes were assessed using the Oswestry Disability Index for low-back pain, the 12-Item Short Form Health Survey, Odom's criteria, and a visual analog scale for pain. Fine-cut CT scans were used to evaluate the progression to fusion.
Results
All patients who received i-FACTOR demonstrated radiographic evidence of bony induction and early incorporation of bone graft. At a mean of 24 months of follow-up (range 15–43 months), 97.5%, 81%, and 100% of patients, respectively, who had undergone single-, double-, and triple-level surgery exhibited fusion at all treated levels. The clinical outcomes demonstrated a statistically significant (p < 0.05) difference between preoperative and postoperative Oswestry Disability Index, 12-Item Short Form Health Survey, and visual analog scores.
Conclusions
The use of i-FACTOR bone graft substitute demonstrates promising results for facilitating successful fusion and improving clinical outcomes in patients who undergo ALIF surgery for degenerative spinal pathologies.
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Affiliation(s)
- Ralph J. Mobbs
- 1NeuroSpineClinic, Prince of Wales Private Hospital; and
- 2Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Monish Maharaj
- 2Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Prashanth J. Rao
- 1NeuroSpineClinic, Prince of Wales Private Hospital; and
- 2Faculty of Medicine, University of New South Wales, Sydney, Australia
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Ding M, Andreasen CM, Dencker ML, Jensen AE, Theilgaard N, Overgaard S. Efficacy of a small cell-binding peptide coated hydroxyapatite substitute on bone formation and implant fixation in sheep. J Biomed Mater Res A 2014; 103:1357-65. [PMID: 25045068 DOI: 10.1002/jbm.a.35281] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 06/12/2014] [Accepted: 07/03/2014] [Indexed: 12/25/2022]
Abstract
Cylindrical critical size defects were created at the distal femoral condyles bilaterally of eight female adult sheep. Titanium implants with 2-mm concentric gaps were inserted and the gaps were filled with one of the four materials: allograft; a synthetic 15-amino acid cell-binding peptide coated hydroxyapatite (ABM/P-15); hydroxyapatite + βtricalciumphosphate+ Poly-Lactic-Acid (HA/βTCP-PDLLA); or ABM/P-15+HA/βTCP-PDLLA. After nine weeks, bone-implant blocks were harvested and sectioned for micro-CT scanning, push-out test, and histomorphometry. Significant bone formation and implant fixation could be observed in all four groups. Interestingly, the microarchitecture of the ABM/P-15 group was significantly different from the control group. Tissue volume fraction and thickness were significantly greater in the ABM/P-15 group than in the allograft group. Bone formation and bone ingrowth to porous titanium implant were not significantly different among the four groups. The ABM/P-15 group had similar shear mechanical properties on implant fixation as the allograft group. Adding HA/βTCP-PDLLA to ABM/P-15 did not significantly change these parameters. This study revealed that ABM/P-15 had significantly bone formation in concentric gap, and its enhancements on bone formation and implant fixation were at least as good as allograft. It is suggested that ABM/P-15 might be a good alternative biomaterial for bone implant fixation in this well-validated critical-size defect gap model in sheep. Nevertheless, future clinical researches should focus on prospective, randomized, controlled trials in order to fully elucidate whether ABM/P-15 could be a feasible candidate for bone substitute material in orthopedic practices.
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Affiliation(s)
- Ming Ding
- Orthopaedic Research Laboratory, Department of Orthopaedic Surgery & Traumatology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark
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29
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Pereira KK, Alves OC, Novaes AB, de Oliveira FS, Yi JH, Zaniquelli O, Wolf-Brandstetter C, Scharnweber D, Variola F, Nanci A, Rosa AL, de Oliveira PT. Progression of Osteogenic Cell Cultures Grown on Microtopographic Titanium Coated With Calcium Phosphate and Functionalized With a Type I Collagen-Derived Peptide. J Periodontol 2013; 84:1199-210. [DOI: 10.1902/jop.2012.120072] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Culpepper BK, Bonvallet PP, Reddy MS, Ponnazhagan S, Bellis SL. Polyglutamate directed coupling of bioactive peptides for the delivery of osteoinductive signals on allograft bone. Biomaterials 2012. [PMID: 23182349 DOI: 10.1016/j.biomaterials.2012.10.046] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Allograft bone is commonly used as an alternative to autograft, however allograft lacks many osteoinductive factors present in autologous bone due to processing. In this study, we investigated a method to reconstitute allograft with osteoregenerative factors. Specifically, an osteoinductive peptide from collagen I, DGEA, was engineered to express a heptaglutamate (E7) domain, which binds the hydroxyapatite within bone mineral. Addition of E7 to DGEA resulted in 9× greater peptide loading on allograft, and significantly greater retention after a 5-day interval with extensive washing. When factoring together greater initial loading and retention, the E7 domain directed a 45-fold enhancement of peptide density on the allograft surface. Peptide-coated allograft was also implanted subcutaneously into rats and it was found that E7DGEA was retained in vivo for at least 3 months. Interestingly, E7DGEA peptides injected intravenously accumulated within bone tissue, implicating a potential role for E7 domains in drug delivery to bone. Finally, we determined that, as with DGEA, the E7 modification enhanced coupling of a bioactive BMP2-derived peptide on allograft. These results suggest that E7 domains are useful for coupling many types of bone-regenerative molecules to the surface of allograft to reintroduce osteoinductive signals and potentially advance allograft treatments.
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Affiliation(s)
- Bonnie K Culpepper
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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31
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Liu Q, Limthongkul W, Sidhu G, Zhang J, Vaccaro A, Shenck R, Hickok N, Shapiro I, Freeman T. Covalent attachment of P15 peptide to titanium surfaces enhances cell attachment, spreading, and osteogenic gene expression. J Orthop Res 2012; 30:1626-33. [PMID: 22504956 DOI: 10.1002/jor.22116] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Accepted: 03/15/2012] [Indexed: 02/04/2023]
Abstract
P15, a synthetic 15 amino acid peptide, mimics the cell-binding domain within the alpha-1 chain of human collagen is being tested in clinical trials to determine if it enhances bone formation in spinal fusions. We hypothesize that covalent attachment of P15 to titanium implants may also serve to promote osseointegration. To test this hypothesis, we measured osteoblast and mesenchymal cell adhesion, proliferation, and maturation on P15 tethered to a titanium (Ti-P15) surface. P15 peptide was covalently bonded to titanium alloy surfaces and incubated with osteoblast like cells. Cell toxicity, adhesion, spreading, and differentiation was then evaluated. Real-time quantitative PCR, Western blot analysis, and fluorescent immunohistochemistry was performed to measure osteoblast gene expression and differentiation. There was no evidence of toxicity. Significant increases in early cell attachment, spreading, and proliferation were observed on the Ti-P15 surface. Increased filapodial attachments, α(2) integrin expression, and phosphorylated focal adhesion kinase immunostaining indicated activation of integrin signaling pathways. qRT-PCR analysis indicated there was significant increase in osteogenic differentiation markers in cells grown on Ti-P15 compared to control-Ti. Western blotting confirmed these findings. Surface modification of titanium with P15 significantly increased cell attachment, spreading, osteogenic gene expression, and differentiation. Results of this study suggest that Ti-P15 has the potential to safely enhance bone formation and promote osseointegration of titanium implants.
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Affiliation(s)
- Qinyi Liu
- Department of Orthopedics, The Second Hospital of Jilin University, Chang Chun, Jilin, China
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Aoki K, Alles N, Soysa N, Ohya K. Peptide-based delivery to bone. Adv Drug Deliv Rev 2012; 64:1220-38. [PMID: 22709649 DOI: 10.1016/j.addr.2012.05.017] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 05/29/2012] [Accepted: 05/29/2012] [Indexed: 01/26/2023]
Abstract
Peptides are attractive as novel therapeutic reagents, since they are flexible in adopting and mimicking the local structural features of proteins. Versatile capabilities to perform organic synthetic manipulations are another unique feature of peptides compared to protein-based medicines, such as antibodies. On the other hand, a disadvantage of using a peptide for a therapeutic purpose is its low stability and/or high level of aggregation. During the past two decades, numerous peptides were developed for the treatment of bone diseases, and some peptides have already been used for local applications to repair bone defects in the clinic. However, very few peptides have the ability to form bone themselves. We herein summarize the effects of the therapeutic peptides on bone loss and/or local bone defects, including the results from basic studies. We also herein describe some possible methods for overcoming the obstacles associated with using therapeutic peptide candidates.
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Affiliation(s)
- Kazuhiro Aoki
- Dept. of Hard Tissue Engineering (Pharmacology), Graduate School, Tokyo Medical & Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
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Shekaran A, García AJ. Extracellular matrix-mimetic adhesive biomaterials for bone repair. J Biomed Mater Res A 2010; 96:261-72. [PMID: 21105174 DOI: 10.1002/jbm.a.32979] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Revised: 09/07/2010] [Accepted: 09/08/2010] [Indexed: 01/12/2023]
Abstract
Limited osseointegration of current orthopedic biomaterials contributes to the failure of implants such as arthroplasties, bone screws, and bone grafts, which present a large socioeconomic cost within the United States. These implant failures underscore the need for biomimetic approaches that modulate host cell-implant material responses to enhance implant osseointegration and bone formation. Bioinspired strategies have included functionalizing implants with extracellular matrix (ECM) proteins or ECM-derived peptides or protein fragments, which engage integrins and direct osteoblast adhesion and differentiation. This review discusses (1) bone ECM composition and key integrins implicated in osteogenic differentiation, (2) the use of implants functionalized with ECM-mimetic peptides/protein fragments, and (3) growth factor-derived peptides to promote the mechanical fixation of implants to bone and to enhance bone healing within large defects.
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Affiliation(s)
- Asha Shekaran
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
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34
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Culpepper BK, Phipps MC, Bonvallet PP, Bellis SL. Enhancement of peptide coupling to hydroxyapatite and implant osseointegration through collagen mimetic peptide modified with a polyglutamate domain. Biomaterials 2010; 31:9586-94. [PMID: 21035181 DOI: 10.1016/j.biomaterials.2010.08.020] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Accepted: 08/07/2010] [Indexed: 01/20/2023]
Abstract
Hydroxyapatite (HA) is a widely-used biomaterial for bone repair due to its high degree of osteoconductivity. However, strategies for improving HA performance by functionalizing surfaces with bioactive factors are limited. In this study, we explored the use of a HA-binding domain (heptaglutamate, "E7") to facilitate coupling of the collagen mimetic peptide, DGEA, to two types of HA-containing materials, solid HA disks and electrospun polycaprolactone matrices incorporating nanoparticulate HA. We found that the E7 domain directed significantly more peptide to the surface of HA and enhanced peptide retention on both materials in vitro. Moreover, E7-modified peptides were retained in vivo for at least two months, highlighting the potential of this mechanism as a sustained delivery system for bioactive peptides. Most importantly, E7-DGEA-coupled HA, as compared with DGEA-HA, enhanced the adhesion and osteoblastic differentiation of mesenchymal stem cells, and also increased new bone formation and direct bone-implant contact on HA disks implanted into rat tibiae. Collectively, these results support the use of E7-DGEA peptides to promote osteogenesis on HA substrates, and further suggest that the E7 domain can serve as a universal tool for anchoring a wide variety of bone regenerative molecules to any type of HA-containing material.
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Affiliation(s)
- Bonnie K Culpepper
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, United States
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Lindley EM, Guerra FA, Krauser JT, Matos SM, Burger EL, Patel VV. Small peptide (P-15) bone substitute efficacy in a rabbit cancellous bone model. J Biomed Mater Res B Appl Biomater 2010; 94:463-468. [PMID: 20578227 DOI: 10.1002/jbm.b.31676] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
P-15 is a synthetic 15-amino acid residue identical to the cell binding domain of type I collagen. P-15 can be adsorbed onto anorganic bovine bone mineral (ABM) and will enhance cell attachment and subsequent cell activation. Although ABM/P-15 has been studied as a bone graft substitute in the oral cavity, its use in orthopedic models has been limited. Thus, this study investigated the efficacy of ABM/P-15 treatment in a rabbit model of long bone cancellous healing. Defects were created in the distal femurs and proximal medial tibiae of rabbits and were filled with either ABMP/P-15 suspended in hydrogel, ABM alone suspended in hydrogel, hydrogel carrier alone, or no graft material. Rabbits were sacrificed at 1, 2, 4, or 8 weeks postsurgery, and the femurs and tibiae were harvested. Histomorphometric analyses indicated that defects treated with ABM/P-15 had significantly larger areas of new bone formation than the other three treatments at 2 and 8 weeks postsurgery. ABM/P-15 treated defects also had significantly more bone growth than defects left empty or filled with ABM alone at 4 weeks postsurgery. Furthermore, histological examination did not reveal acute inflammatory infiltrate cells in any of the treatment conditions. These results are consistent with the findings of ABM/P-15 use in human oral-maxillofacial studies and in large animal spine fusion models.
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Affiliation(s)
- Emily M Lindley
- The Spine Center, Department of Orthopedics, University of Colorado, Denver, Colorado, USA
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Evaluation of ABM/P-15 versus autogenous bone in an ovine lumbar interbody fusion model. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2010; 19:2156-63. [PMID: 20694847 DOI: 10.1007/s00586-010-1546-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 06/15/2010] [Accepted: 07/25/2010] [Indexed: 10/19/2022]
Abstract
A prospective, randomized study was performed in an ovine model to compare the efficacy of an anorganic bovine-derived hydroxyapatite matrix combined with a synthetic 15 amino acid residue (ABM/P-15) in facilitating lumbar interbody fusion when compared with autogenous bone harvested from the iliac crest. P-15 is a biomimetic to the cell-binding site of Type-I collagen for bone-forming cells. When combined with ABM, it creates the necessary scaffold to initiate cell invasion, binding, and subsequent osteogenesis. In this study, six adult ewes underwent anterior-lateral interbody fusion at L3/L4 and L4/L5 using PEEK interbody rings filled with autogenous bone at one level and ABM/P-15 at the other level and no additional instrumentation. Clinical CT scans were obtained at 3 and 6 months; micro-CT scans and histomorphometry analyses were performed after euthanization at 6 months. Clinical CT scan analysis showed that all autograft and ABM/P-15 treated levels had radiographically fused outside of the rings at the 3-month study time point. Although the clinical CT scans of the autograft treatment group showed significantly better fusion within the PEEK rings than ABM/P-15 at 3 months, micro-CT scans, clinical CT scans, and histomorphometric analyses showed there were no statistical differences between the two treatment groups at 6 months. Thus, ABM/P-15 was as successful as autogenous bone graft in producing lumbar spinal fusion in an ovine model, and it should be further evaluated in clinical studies.
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Mittal A, Negi P, Garkhal K, Verma S, Kumar N. Integration of porosity and bio-functionalization to form a 3D scaffold: cell culture studies and
in vitro
degradation. Biomed Mater 2010; 5:045001. [DOI: 10.1088/1748-6041/5/4/045001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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