Potential of endogenous regenerative technology for in situ regenerative medicine.

Endogenous regenerative technology (Endoret) involves the use of patient's own biologically active proteins, growth factors and biomaterial scaffolds for therapeutic purposes. This technology provides a new approach for the stimulation and acceleration of tissue healing and bone regeneration. The versatility and biocompatibility of using patient-derived fibrin scaffold as an autologous, biocompatible and biodegradable drug delivery system open the door to a personalized medicine that is currently being used in numerous medical and scientific fields including dentistry, oral implantology, orthopaedics, ulcer treatment, sports medicine and tissue engineering among others. This review discusses the state of the art and new directions in the use of endogenous technology in the repair and regeneration of injured tissues by means of a controlled and local protein and growth factor delivery. The next generations of engineering strategies together with some of the most interesting therapeutic applications are discussed together with the future challenges in the field.

[1]  Teruo Okano,et al.  Pulsatile drug release control using hydrogels. , 2002, Advanced drug delivery reviews.

[2]  G. Watzek,et al.  Platelets stimulate proliferation of bone cells: involvement of platelet-derived growth factor, microparticles and membranes. , 2002, Clinical oral implants research.

[3]  R. Lysens,et al.  Patellar Tendinopathy in Athletes , 2005, Sports medicine.

[4]  S. Aota,et al.  Fibronectin regulates calvarial osteoblast differentiation. , 1996, Journal of cell science.

[5]  Gorka Orive,et al.  Drug delivery in biotechnology: present and future. , 2003, Current opinion in biotechnology.

[6]  J. Rubenstein,et al.  Ten-year results for Brånemark implants immediately loaded with fixed prostheses at implant placement. , 1997, The International journal of oral & maxillofacial implants.

[7]  R. Jaffin,et al.  The excessive loss of Branemark fixtures in type IV bone: a 5-year analysis. , 1991, Journal of periodontology.

[8]  Keyser Je Diabetic wound healing and limb salvage in an outpatient wound care program. , 1993 .

[9]  R. Zaninetti,et al.  Effect of platelet‐rich plasma on migration and proliferation of SaOS‐2 osteoblasts: role of platelet‐derived growth factor and transforming growth factor‐β , 2006 .

[10]  David J Mooney,et al.  Integrated approach to designing growth factor delivery systems , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  T. Nishihara,et al.  Platelet-rich plasma enhances human osteoblast-like cell proliferation and differentiation. , 2005, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[12]  M. Montjovent,et al.  Fetal bone cells for tissue engineering. , 2004, Bone.

[13]  Yasuhiko Tabata,et al.  Tissue regeneration based on growth factor release. , 2003, Tissue engineering.

[14]  G. Murrell,et al.  The Roles of Growth Factors in Tendon and Ligament Healing , 2003, Sports medicine.

[15]  R. Langer,et al.  Tissue engineering: current state and perspectives , 2004, Applied Microbiology and Biotechnology.

[16]  Yunsong Liu,et al.  Injectable tissue-engineered bone composed of human adipose-derived stromal cells and platelet-rich plasma. , 2008, Biomaterials.

[17]  Dean Morton,et al.  Consensus statements and recommended clinical procedures regarding loading protocols for endosseous dental implants. , 2004, The International journal of oral & maxillofacial implants.

[18]  Y. M. Lee,et al.  Controlled release of platelet-derived growth factor-BB from chondroitin sulfate-chitosan sponge for guided bone regeneration. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[19]  J. Alió,et al.  Symptomatic Dry Eye Treatment with Autologous Platelet-Rich Plasma , 2007, Ophthalmic Research.

[20]  T. Orfeo,et al.  Osteonectin in matrix remodeling. A plasminogen-osteonectin-collagen complex. , 1994, The Journal of biological chemistry.

[21]  S. Giannini,et al.  Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions , 2010, Knee Surgery, Sports Traumatology, Arthroscopy.

[22]  R. Haas,et al.  Sinus grafting with autogenous platelet-rich plasma and bovine hydroxyapatite. A histomorphometric study in minipigs. , 2003, Clinical oral implants research.

[23]  A. Nurden,et al.  Reciprocal Actions of Platelet-Secreted TGF-&bgr;1 on the Production of VEGF and HGF by Human Tendon Cells , 2007, Plastic and reconstructive surgery.

[24]  T. Hansen,et al.  Effect of platelet concentration in platelet-rich plasma on peri-implant bone regeneration. , 2004, Bone.

[25]  T. Hewett,et al.  Noncontact anterior cruciate ligament injuries: risk factors and prevention strategies. , 2000, The Journal of the American Academy of Orthopaedic Surgeons.

[26]  S. Rafii,et al.  Trophic Effects of Platelets on Cultured Endothelial Cells are Mediated by Platelet-associated Fibroblast Growth Factor-2 (FGF-2) and Vascular Endothelial Growth Factor (VEGF) , 2002, Thrombosis and Haemostasis.

[27]  E. Canalis,et al.  Effect of insulinlike growth factor I on DNA and protein synthesis in cultured rat calvaria. , 1980, The Journal of clinical investigation.

[28]  P I Brånemark,et al.  A 15-year study of osseointegrated implants in the treatment of the edentulous jaw. , 1981, International journal of oral surgery.

[29]  N. Ishiguro,et al.  Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis--a preliminary result of three cases. , 2004, Bone.

[30]  A. Reddi,et al.  Role of fibronectin in collagenous matrix-induced mesenchymal cell proliferation and differentiation in vivo. , 1981, Experimental cell research.

[31]  C. Kirker-Head,et al.  Potential applications and delivery strategies for bone morphogenetic proteins. , 2000, Advanced drug delivery reviews.

[32]  G. Orive,et al.  Effectiveness of autologous preparation rich in growth factors for the treatment of chronic cutaneous ulcers. , 2008, Journal of biomedical materials research. Part B, Applied biomaterials.

[33]  Y. Shimabukuro,et al.  Periodontal Regeneration by Fgf-2 (bfgf) in Primate Models on Behalf Of: International and American Associations for Dental Research Periodontal Regeneration by Fgf-2 (bfgf) in Primate Models , 2001 .

[34]  S. Teitelbaum,et al.  Recruitment of osteoclast precursors by purified bone matrix constituents , 1982, The Journal of cell biology.

[35]  Robert Langer,et al.  Polymeric Biomaterials in Tissue Engineering , 2008, Pediatric Research.

[36]  P. Nurden,et al.  Autologous preparations rich in growth factors promote proliferation and induce VEGF and HGF production by human tendon cells in culture , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[37]  J. Palmblad,et al.  Angiogenesis Research: Guidelines for Translation to Clinical Application , 2001, Thrombosis and Haemostasis.

[38]  P. Aspenberg,et al.  How can one platelet injection after tendon injury lead to a stronger tendon after 4 weeks?: Interplay between early regeneration and mechanical stimulation , 2006, Acta orthopaedica.

[39]  S. Atri,et al.  Use of homologous platelet factors in achieving total healing of recalcitrant skin ulcers. , 1990, Surgery.

[40]  D. Kingsley,et al.  The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. , 1994, Genes & development.

[41]  D. Caborn,et al.  Articular Cartilage Changes Seen With Magnetic Resonance Imaging-Detected Bone Bruises Associated With Acute Anterior Cruciate Ligament Rupture , 1998, The American journal of sports medicine.

[42]  A. Beaulieu,et al.  Human plasma fibronectin potentiates the mitogenic activity of platelet‐derived growth factor and complements its wound healing effects , 2003, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[43]  D. Knighton,et al.  Amputation prevention in a high-risk population through comprehensive wound-healing protocol. , 1989, Archives of physical medicine and rehabilitation.

[44]  Michelle Urwin,et al.  Estimating the burden of musculoskeletal disorders in the community: the comparative prevalence of symptoms at different anatomical sites, and the relation to social deprivation , 1998, Annals of the rheumatic diseases.

[45]  E. Anitua,et al.  Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retrospective cohort study. , 2008, Clinical and experimental rheumatology.

[46]  G. Reed Platelet secretory mechanisms. , 2004, Seminars in thrombosis and hemostasis.

[47]  E. Anitua Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. , 1999, The International journal of oral & maxillofacial implants.

[48]  Gorka Orive,et al.  Biomaterials for promoting brain protection, repair and regeneration , 2009, Nature Reviews Neuroscience.

[49]  G. Orive,et al.  Five-year clinical evaluation of short dental implants placed in posterior areas: a retrospective study. , 2008, Journal of periodontology.

[50]  Rall Kl,et al.  A STUDY OF LONG TERM EFFECTS OF FOOTBALL INJURY TO THE KNEE. , 1964 .

[51]  K. Burridge,et al.  Formation of focal adhesions by osteoblasts adhering to different substrata. , 1994, Experimental cell research.

[52]  T. Kawase,et al.  Platelet-rich plasma contains high levels of platelet-derived growth factor and transforming growth factor-beta and modulates the proliferation of periodontally related cells in vitro. , 2003, Journal of periodontology.

[53]  A. Weyrich,et al.  Platelets, endothelial cells, inflammatory chemokines, and restenosis: complex signaling in the vascular play book. , 2002, Circulation.

[54]  S. Hardy,et al.  Impaired bone formation in transgenic mice resulting from altered integrin function in osteoblasts. , 2000, Developmental biology.

[55]  R. Genco,et al.  Platelet-derived growth factor-modulated guided tissue regenerative therapy. , 1995, Journal of periodontology.

[56]  T A Einhorn,et al.  Growth Factor Regulation of Fracture Repair , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[57]  J. Tessmar,et al.  Matrices and scaffolds for protein delivery in tissue engineering. , 2007, Advanced drug delivery reviews.

[58]  G. Vunjak‐Novakovic,et al.  Engineering complex tissues. , 2006, Tissue engineering.

[59]  David J Mooney,et al.  VEGF Scaffolds Enhance Angiogenesis and Bone Regeneration in Irradiated Osseous Defects , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[60]  F. Cerra,et al.  Stimulation of repair in chronic, nonhealing, cutaneous ulcers using platelet-derived wound healing formula. , 1990, Surgery, gynecology & obstetrics.

[61]  Y. Tabata,et al.  Augmented bone regeneration activity of platelet-rich plasma by biodegradable gelatin hydrogel. , 2005, Tissue engineering.

[62]  D van Steenberghe,et al.  Factors related to success and failure rates at 3-year follow-up in a multicenter study of overdentures supported by Brånemark implants. , 1995, The International journal of oral & maxillofacial implants.

[63]  Francesca Ungaro,et al.  Controlled drug delivery in tissue engineering. , 2008, Advanced drug delivery reviews.

[64]  Eleftherios Tsiridis,et al.  Current concepts of molecular aspects of bone healing. , 2005, Injury.

[65]  C. Heldin,et al.  Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB. , 2007, The Biochemical journal.

[66]  H. Kantarjian,et al.  Biology of platelet-derived growth factor and its involvement in disease. , 2006, Mayo Clinic proceedings.

[67]  V. Driver,et al.  A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. , 2006, Ostomy/wound management.

[68]  Paquita Nurden,et al.  Autologous platelets as a source of proteins for healing and tissue regeneration , 2003, Thrombosis and Haemostasis.

[69]  B. Rangert,et al.  Immediate/early loading of dental implants: a report from the Sociedad Española de Implantes World Congress consensus meeting in Barcelona, Spain, 2002. , 2003, Clinical implant dentistry and related research.

[70]  P. Nurden,et al.  New insights into and novel applications for platelet-rich fibrin therapies. , 2006, Trends in biotechnology.

[71]  G. Orive,et al.  The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. , 2007, Biomaterials.

[72]  David J Mooney,et al.  Cell instructive polymers. , 2006, Advances in biochemical engineering/biotechnology.

[73]  D. Margolis,et al.  Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. , 2001, Diabetes care.

[74]  Gorka Orive,et al.  Delivering growth factors for therapeutics. , 2008, Trends in pharmacological sciences.

[75]  J. Benoit,et al.  Intraseptal implantation of NGF-releasing microspheres promote the survival of axotomized cholinergic neurons. , 2000, Biomaterials.

[76]  Benjamin M. Wu,et al.  Biomimetic apatite-coated alginate/chitosan microparticles as osteogenic protein carriers. , 2009, Biomaterials.

[77]  M. de la Fuente,et al.  Autologous fibrin matrices: a potential source of biological mediators that modulate tendon cell activities. , 2006, Journal of biomedical materials research. Part A.

[78]  C. Weber,et al.  Platelets as Immune Cells: Bridging Inflammation and Cardiovascular Disease , 2007, Circulation research.

[79]  F. Andreopoulos,et al.  Delivery of basic fibroblast growth factor (bFGF) from photoresponsive hydrogel scaffolds. , 2006, Biomaterials.

[80]  Ernesto A. Lee,et al.  Atraumatic ridge expansion and implant site preparation with motorized bone expanders. , 2006, Practical procedures & aesthetic dentistry : PPAD.

[81]  J. Alió,et al.  Use of autologous platelet-rich plasma in the treatment of dormant corneal ulcers. , 2007, Ophthalmology.

[82]  I. Zachary,et al.  The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease , 2005, Genome Biology.

[83]  R. Ross,et al.  The biology of platelet-derived growth factor , 1986, Cell.

[84]  E. Carson,et al.  Revision anterior cruciate ligament surgery. , 1999, Clinics in sports medicine.

[85]  P Aebischer,et al.  Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. , 2000, Human gene therapy.

[86]  L. Ye,et al.  HGF enhanced proliferation and differentiation of dental pulp cells. , 2006, Journal of endodontics.

[87]  G. Orive,et al.  The effects of PRGF on bone regeneration and on titanium implant osseointegration in goats: a histologic and histomorphometric study. , 2009, Journal of biomedical materials research. Part A.

[88]  R A Jaffin,et al.  Immediate loading of implants in partially and fully edentulous jaws: a series of 27 case reports. , 2000, Journal of periodontology.

[89]  Michael T Longaker,et al.  Hypertrophic Scar Formation Following Burns and Trauma: New Approaches to Treatment , 2007, PLoS medicine.

[90]  M. Otto,et al.  [Growth stimulation of human osteoblast-like cells by thrombocyte concentrates in vitro]. , 2002, Mund-, Kiefer- und Gesichtschirurgie : MKG.

[91]  Gorka Orive,et al.  Techniques: new approaches to the delivery of biopharmaceuticals. , 2004, Trends in pharmacological sciences.

[92]  J. Lanciego,et al.  Effective GDNF brain delivery using microspheres--a promising strategy for Parkinson's disease. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[93]  X. Holy,et al.  Platelet lysates promote mesenchymal stem cell expansion: A safety substitute for animal serum in cell‐based therapy applications , 2005, Journal of cellular physiology.

[94]  P Schärer,et al.  Immediate occlusal loading of Brånemark implants applied in various jawbone regions: a prospective, 1-year clinical study. , 2001, Clinical implant dentistry and related research.

[95]  D J Mooney,et al.  Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis , 2007, Journal of thrombosis and haemostasis : JTH.

[96]  T. Pavelko,et al.  Treatment of Chronic Elbow Tendinosis with Buffered Platelet-Rich Plasma , 2006, The American journal of sports medicine.

[97]  J. Lou,et al.  Bone regeneration by implantation of adipose-derived stromal cells expressing BMP-2. , 2007, Biochemical and biophysical research communications.

[98]  B. Snyder,et al.  Collagen‐platelet rich plasma hydrogel enhances primary repair of the porcine anterior cruciate ligament , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[99]  M. Ueda,et al.  Osteogenic potential of injectable tissue-engineered bone: a comparison among autogenous bone, bone substitute (Bio-oss), platelet-rich plasma, and tissue-engineered bone with respect to their mechanical properties and histological findings. , 2005, Journal of biomedical materials research. Part A.

[100]  Paroma Basu News Feature: Technologies that deliver , 2003, Nature Medicine.

[101]  T. Morotomi,et al.  Formation of dentin-like particles in dentin defects above exposed pulp by controlled release of fibroblast growth factor 2 from gelatin hydrogels. , 2007, Journal of endodontics.

[102]  M. Ueda,et al.  Translational Research for Injectable Tissue-Engineered Bone Regeneration Using Mesenchymal Stem Cells and Platelet-Rich Plasma: From Basic Research to Clinical Case Study , 2004, Cell transplantation.

[103]  J. Hatzfeld,et al.  Fibrinogen potentiates the effect of interleukin-3 on early human hematopoietic progenitors. , 1993, Blood.

[104]  E. Brey,et al.  Sustained delivery of FGF-1 increases vascular density in comparison to bolus administration. , 2009, Microvascular research.

[105]  D. Thompson,et al.  Presence of messenger ribonucleic acid encoding osteocalcin, a marker of bone turnover, in bone marrow megakaryocytes and peripheral blood platelets. , 1994, Endocrinology.

[106]  W. V. van Gemert,et al.  Autologous platelet‐derived growth factors (platelet‐rich plasma) as an adjunct to mucosal advancement flap in high cryptoglandular perianal fistulae: a pilot study , 2011, Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland.

[107]  G. Brunner,et al.  Extracellular regulation of TGF-β activity in wound repair: growth factor latency as a sensor mechanism for injury , 2004, Thrombosis and Haemostasis.

[108]  P. Nurden,et al.  Platelets and wound healing. , 2008, Frontiers in bioscience : a journal and virtual library.

[109]  A. Singer,et al.  Cutaneous wound healing. , 1999, The New England journal of medicine.

[110]  R Langer,et al.  Prospects for organ and tissue replacement. , 2001, JAMA.

[111]  S. Werner,et al.  Regulation of wound healing by growth factors and cytokines. , 2003, Physiological reviews.

[112]  G. Orive,et al.  Clinical Outcome of Immediately Loaded Dental Implants Bioactivated With Plasma Rich in Growth Factors: A 5-Year Retrospective Study , 2008 .

[113]  C. Conover,et al.  In vitro studies of insulin-like growth factor I and bone. , 2000, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[114]  W. Mark Saltzman,et al.  Building drug delivery into tissue engineering design , 2002, Nature Reviews Drug Discovery.

[115]  M. Hincke,et al.  Fibrin: a versatile scaffold for tissue engineering applications. , 2008, Tissue engineering. Part B, Reviews.

[116]  G. Evans,et al.  In vivo osteogenic potential of human adipose-derived stem cells/poly lactide-co-glycolic acid constructs for bone regeneration in a rat critical-sized calvarial defect model. , 2007, Tissue engineering.

[117]  C A Heath,et al.  Cells for tissue engineering. , 2000, Trends in biotechnology.

[118]  I. Mujika,et al.  Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. , 2003, Medicine and science in sports and exercise.

[119]  Takaaki Tanaka,et al.  Repair of segmental bone defects in rabbit tibiae using a complex of beta-tricalcium phosphate, type I collagen, and fibroblast growth factor-2. , 2006, Biomaterials.

[120]  G. Intini,et al.  Calcium Sulfate and Platelet-Rich Plasma make a novel osteoinductive biomaterial for bone regeneration , 2007, Journal of Translational Medicine.

[121]  H. Redmond,et al.  Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[122]  J. Freyssinet,et al.  Procoagulant Microparticles: Disrupting the Vascular Homeostasis Equation? , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[123]  E. Anitua Enhancement of osseointegration by generating a dynamic implant surface. , 2006, The Journal of oral implantology.

[124]  K. March,et al.  Adipose Stromal Cells and Platelet-Rich Plasma Therapies Synergistically Increase Revascularization during Wound Healing , 2009, Plastic and reconstructive surgery.

[125]  T. Wolter,et al.  Platelet-rich plasma in burns. , 2010, Burns : journal of the International Society for Burn Injuries.

[126]  Helen H. Lu,et al.  Controlled delivery of platelet-rich plasma-derived growth factors for bone formation. , 2008, Journal of biomedical materials research. Part A.

[127]  A. D'Angelo,et al.  Fibronectin and laminin enhance gingival cell attachment to dental implant surfaces in vitro. , 1995, The International journal of oral & maxillofacial implants.

[128]  N P Lang,et al.  The significance of angiogenesis in guided bone regeneration. A case report of a rabbit experiment. , 1997, Clinical oral implants research.

[129]  G. Orive,et al.  A lateral approach for sinus elevation using PRGF technology. , 2009, Clinical implant dentistry and related research.

[130]  Helen H. Lu,et al.  Differential growth factor retention by platelet-rich plasma composites. , 2004, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[131]  E. Anitua,et al.  Ultrasonic ostectomy for the surgical approach of the maxillary sinus: a technical note. , 1998, The International journal of oral & maxillofacial implants.

[132]  P. Price Vitamin K-dependent formation of bone Gla protein (osteocalcin) and its function. , 1985, Vitamins and hormones.

[133]  G. Reiber,et al.  Pathways to Diabetic Limb Amputation: Basis for Prevention , 1990, Diabetes Care.

[134]  D. Connell,et al.  Medial epicondylitis: is ultrasound guided autologous blood injection an effective treatment? , 2006, British Journal of Sports Medicine.

[135]  H. Mohammed,et al.  Platelet rich plasma (PRP) enhances anabolic gene expression patterns in flexor digitorum superficialis tendons , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[136]  P. Verhaegen,et al.  Effect of Platelet Rich Plasma and Fibrin Sealant on Facial Nerve Regeneration in a Rat Model , 2007, The Laryngoscope.

[137]  Michael S. Goldberg,et al.  Nanostructured materials for applications in drug delivery and tissue engineering , 2007, Journal of biomaterials science. Polymer edition.

[138]  G. Orive,et al.  5-year clinical experience with BTI dental implants: risk factors for implant failure. , 2008, Journal of clinical periodontology.

[139]  F. Savoie,et al.  Common Elbow Injuries in Sport , 1998, Sports Medicine.

[140]  S. Trippel Potential role of insulinlike growth factors in fracture healing. , 1998, Clinical orthopaedics and related research.

[141]  J. Massagué,et al.  The transforming growth factor-beta family. , 1990, Annual review of cell biology.