2.79J/3.96J/20.441J/HST522J Biomaterials-Tissue Interactions Prof. Myron Spector Harvard Medical School Director, Orthopedics Research Laboratory Brigham and Women’s Hospital Prof. Ioannis Yannas MIT Departments of Mechanical and Biological Engineering Fibers and Polymers Laboratory2.79J/3.96J/20.441J/HST522J Biomaterials- Tissue Interactions INTRODUCTION • How are biomaterials used? • Today’s brief survey: from organs to cells.How are biomaterials used? Today’s brief survey: from organ to cell outline of survey A. Five Therapies for the Missing Organ Examples of permanent implants Examples of regenerated organs B. Tissue and organ regenerationviewed as processes of chemical synthesis. C. What is the mechanism of organ regeneration? D. Cell-matrix interactions. E. The unit cell process.A. Five Therapies for the Missing Organ 1. Transplantation (e.g., kidney transplant, heart transplant,liver transplant) 2. Autografting (e.g., heart bypass, skin grafting). 3. Permanent implants (e.g., hip prosthesis, pacemaker, breast implant) 4. In vitro synthesis (e.g., epidermis) 5. In vivo synthesis or regeneration (e.g., skin, nerves,conjunctiva). ”Regenerative medicine”. Remarks: Biomaterials are used in therapies #3, 4 and 5. Tissue engineering includes therapies #4 and 5.Not an implant!Organ Replacement Therapy Class 3 : Example of permanent implant Figure by MIT OpenCourseWare.Organ Replacement Therapy Class 3 : Another example of permanent implant Image removed due to copyright restrictions. Boston Globe newspaper graphic about FDA approval for the AbioCor artificial heart.Image removed due to copyright restrictions. Photo of severe burn victim. Organ Replacement Therapy Class 5: Examples of regeneration of the injured skin organ Severely burned victim heals injury by contraction and scar formationStudy of skin regeneration A device that regenerates skin in burned patients, patients undergoing plastic surgery and treats chronic skin wound patients is currently used clinicallyVisualization of device. Bilayer device to regenerate skin Top layer protects wounded site while bottom layer induces Yannas et al., regeneration of dermis Science, 1982 Figure by MIT OpenCourseWare.A case of skin regeneration studied by Dr. Andrew Byrd, Bristol, UK Burn victim, a female teenager, was treated by 1) excision of burn scar, 2) grafting of a biologically active scaffold (template) and 3) regeneration of skin in place of burn scar (Several subsequent slides removed due to copyright restrictions.)Several subsequent slides removed due to copyright restrictions. 1. Left breast failed to develop due to mechanical stresses of scar on it. 2. Surgeon has excised the entire scar around breast generating a deep skin wound 3. Wounds have been grafted with the bilayer device (silicone layer outside; scaffold inside). Side view shows that left breast has now erupted. 4. Top view emphasizes the shiny silicone layer outside. 5. New vascularized skin has grown two weeks after grafting of scaffold. Two-stage procedure: (1) Graft scaffold to regenerate dermis; (2) Graft an epidermal autograft on top of new dermis. “Alligator” pattern disappears later.Two cases of massively burnt patients (treated by Dr JF Burke, MGH) 1. Six-year-old boy burned massively was treated in upper abdomen with own skin (meshed autograft) and in lower abdomen with template. 2. Middle-aged man burned in industrial fire, lost skin in right side of face was treated with template.KINETICS OF SKIN SYNTHESIS II. Images removed due to copyright restrictions. Scaffold degraded; diffuses away Butler et al., 1998No scaffold This wound is contracting vigorously Scaffold This wound is not contracting 100 μm 100 μm Troxel, MIT Thesis, 1994 Contraction blocked by active scaffold.Study of peripheral nerve regeneration A device that treats nerve paralysis in human limbs by regenerating the injured nerve is currently used in clinicsRegeneration of peripheral nerves in patients with limb paralysis Rat model for study of nerve regeneration following complete transection of sciatis nerve Landstrom, Aria. “Nerve Regeneration Induced by Collagen-GAG Matrix in Collagen Tubes.” MS Thesis, MIT, 1994.Nerve chamber filled with scaffold used to reconnect cut nerves Landstrom, Aria. “Nerve Regeneration Induced by Collagen-GAG Matrix in Collagen Tubes.” MS Thesis, MIT, 1994.Example of good nerve regeneration axons Photo removed due to copyright restrictions. scaffold inside nerve chamber degraded optimally leading to regeneration of new nerve throughout cross sectionExample of poor nerve regeneration axons Photo removed due to copyright restrictions. undegraded scaffold in the center of the new nerve blocks regeneration of axonsWell-regenerated nervePoorly regenerated nerve 15-20 myofibroblast layers25 μm 1 myofibroblast layer 25 μm Copyright (c) 2000 Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. Reprinted with permission of John Wiley & Sons., Inc. A poorly regenerated nerve is surrounded Chamberlainby a thick layer of contractile cells. et al., 2000Study of kidney regeneration Preliminary data with rat kidney . Blocking of wound contractionand scar inhibition in adult rat kidneyrat kidney wound model---3-mm diam. perforations grafted with scaffold ungrafted EXPERIMENTAL ARRANGEMENT FOR STUDY OF SCAR INHIBITION IN KIDNEY Hill et al., 2003 MIT Masters ThesisRat kidney UNTREATED TREATED WITH SCAFFOLD scar formation (blue) significantly smaller scar (blue) fibrotic tissue stains blue contraction of perimeter → reduced perimeter contraction Hill et al., 2003 MIT Masters ThesisStudy of liver regeneration Preliminary data with rat kidney . Blocking of wound contraction and scar inhibition in adult rat kidneySchematic of Wound Model in Adult Mouse Liver 3. Scaffold deployed Inside defect 1. Full-thickness biopsy of left lobe 2. Cylindrical scaffold loaded into delivery device ScaffoldABDC liver partially closed wound liver fresh wound Spontaneously healed mouse liver 4 weeks following dissection of lobe. Gross view. Histology (trichrome stain) shows fibrotic tissue (blue) lining edges of closed wound.Sutures are used to monitor wound contraction in adult mouse liver A BCDEE’FF’G’GGTime = 0 daysTime=7 daysContraction of wounded adult mouse liver is blocked following grafting of scaffold (4 weeks’ data). Scaffold is extremely compliant; does not act as a mechanical splint. A B In the absence of In the presence of