Use of Conditioned Extracellular Matrix as a Tissue-engineered Tumor Matrisome for Prostate Cancer and Melanoma Immunotherapy.

BACKGROUND/AIM: Decellularized extracellular matrix (ECM) acts as a depot for biochemical factors when conditioned by the growth of cells that are subsequently removed, and in the case of tumors, this ECM depot is known as the matrisome. This study was undertaken to determine whether a tissue-engineered matrisome could be used as an antigenic depot to stimulate protective immunity against tumor regrowth and metastasis following surgical reduction of the tumor. MATERIALS AND METHODS: Using two transplanted tumor cell models, the PAIII rat model of prostate cancer and the B16F1 mouse model of melanoma, mice were administered either media (control), a suspension of inactivated tumor cells, extracellular matrix (SIS), or a matrisome engineered through growth and removal of tumor cells on SIS that was then implanted either directly onto the resected tumor bed or at an anatomical site distant to the tumor bed. Tumor weights were determined at 21 days (rats) and at 17 days (mice), and the number of metastatic foci on the lungs were enumerated at 21 days in rats. RESULTS: Data showed that for both PAIII and B16F1 tumors, mean PAIII and B16F1 tumor weights were significantly reduced for vaccinated animals compared to controls. Furthermore, significantly fewer metastatic foci from PAIII tumors were present on the lungs in vaccinated rats compared to controls. CONCLUSION: Antigens within the tissue-engineered matrisome stimulated an inhibitory response to tumor growth; this strategy should be explored further as a means of cancer immunotherapy.

Lack of immunogenicity of xenogeneic DNA from porcine biomaterials.

Background: Clinically useful biomaterials are derived from xenogeneic extracellular matrices, but extensive processes often used to remove all residual DNA are detrimental to their proper biological function. We hypothesized that deliberate and repeated injection of DNA extracted from clinically implantable, xenogeneic extracellular matrices might elicit an immune response in a well-established murine model that could ultimately lead to altered extracellular matrix remodeling. Methods: DNA was purified from unprocessed porcine extracellular matrices and processed extracellular matrices before sterilization (aseptic) and after sterilization. Groups of 10 mice were injected with these 3 purified DNAs and 3 controls: (1) DNA from E. coli; (2) DNA from unprocessed porcine extracellular matrices combined with interleukin-12 and methylated bovine serum albumin and emulsified in incomplete Freund's adjuvant; and (3) buffered saline. Immunizations occurred every 2 weeks for a total of 3 injections. Local cytokines and systemic anti-DNA antibodies were quantified 3 and 7 days after final injection. Results: The DNA extracted from unprocessed, aseptic, or sterilized porcine extracellular matrices failed to elicit a rejection response, and only with significant, proinflammatory adjuvant activation could such a response be seen. Without the adjuvants, biomaterial-derived DNA resulted in a mild accommodation cytokine response locally and no systemic anti-DNA antibody expression even at doses approximately 100-fold larger than would be clinically likely via extracellular matrix implantation. Conclusion: The immunological safety of porcine extracellular matrix biomaterials appears not to be related to DNA residues present. Such biomaterials need not be extensively processed, likely leading to detrimental changes in their bioactivity, solely in an effort to remove the mammalian DNA.

Characterization of the local wound environment following treatment of chronic leg ulcers with SIS wound matrix.

BACKGROUND: The SIS Wound Matrix (SISWM) has been shown to improve healing of chronic ulcers over standard of care. In this study, we tested the hypothesis that chronic venous ulcers responsive to treatment with SISWM would more closely mimic an acute wound state as opposed to unresponsive ulcers. METHODS: Serum and wound exudate were collected at baseline and then weekly for up to 12 weeks from 12 patients receiving multiple applications of the SISWM. Levels of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-12), pro-inflammatory cytokines (IL-1ß, TNF-α, IL-8), and transforming growth factor beta (TGF-ß1) were evaluated. A variety of Th1/Th2 cytokines were also assayed, as were systemic anti-SIS and anti-α-gal antibody titers. RESULTS: Seven of the 12 patients eventually healed their wounds. Results showed significant decreases in MMP-1, MMP-2, MMP-3, MMP-9, TNF-α and IL-8, and significant increases in TGF-ß1 in wounds responding to treatment with the SISWM versus wounds that did not respond to treatment. None of the 12 patients formed a measurable serum antibody response to the SISWM. CONCLUSIONS: These data show that SISWM does not lead to immune system recognition or sensitization to the matrix and that wounds that went on to heal following treatment were characterized by a more acute wound state. The study confirms that the wound environment is important to healing and that turning a wound toward an acute biochemical state is key to the healing process.

Amino acid-based Poly(ester urea) copolymer films for hernia-repair applications.

The use of degradable materials is required to address current performance and functionality shortcomings from biologically-derived tissues and non-resorbable synthetic materials used for hernia mesh repair applications. Herein a series of degradable l-valine-co-l-phenylalanine poly(ester urea) (PEU) copolymers were investigated for soft-tissue repair. Poly[(1-VAL-8)0.7-co-(1-PHE-6)0.3] showed the highest uniaxial mechanical properties (332.5 ±â€¯3.5 MPa). Additionally, l-valine-co-l-phenylalanine poly(ester urea)s were blade coated on small intestine submucosa extracellular matrix (SIS-ECM) and found to enhance the burst test mechanical properties of SIS-ECM in composite films (force at break between 102.6 ±â€¯6.5-151.4 ±â€¯11.3 N). Free standing films of l-valine-co-l-phenylalanine PEUs were found to have superior extension at break when compared to SIS-ECM (averages between 1.2 and 1.9 cm and 1.2 cm respectively). Fibroblast (L-929) spreading, proliferation, and improved attachment over control were observed without toxicity in vitro, while a reduced inflammatory response at both 7 and 14 days post-implant was observed for poly[(1-VAL-8)⁠0.7-co-(1-PHE-6)⁠0.3] when compared to polypropylene in an in vivo rat hernia model. These results support the use of PEU copolymers as free-standing films or as composite materials in soft-tissue applications for hernia-repair.

Contemporary concepts in hernia prevention: Selected proceedings from the 2017 International Symposium on Prevention of Incisional Hernias.

Incisional hernia is a frequent complication of midline laparotomy and enterostomal creation and is associated with high morbidity, decreased quality of life, and high costs. The International Symposium on Incisional Hernia Prevention was held October 19-20, 2017, at the InterContinental Hotel in San Francisco, CA, hosted by the Department of Surgery, University of California, San Francisco. One hundred and three attendees included general and plastic surgeons from 9 countries, including principal participants for several of the seminal studies in the field. Over the course of the 2-day meeting, there were 38 oral presentations, 3 keynote lectures, and 2 panel discussions. The Symposium was a combination of new information but also a comprehensive review of the existing data so as to assess the current state of the field and to set the stage for future research. Further, the Symposium sought to increase awareness and thus emphasize the importance of preventing the formation of incisional and enterostomal hernias.

The Role of miR-126 in Critical Limb Ischemia Treatment Using Adipose-Derived Stem Cell Therapeutic Factor Concentrate and Extracellular Matrix Microparticles.

BACKGROUND Paracrine factors secreted by adipose-derived stem cells can be captured, fractionated, and concentrated to produce therapeutic factor concentrate (TFC). The present study examined whether TFC effects could be enhanced by combining TFC with a biological matrix to provide sustained release of factors in the target region. MATERIAL AND METHODS Unilateral hind limb ischemia was induced in rabbits. Ischemic limbs were injected with either placebo control, TFC, micronized small intestinal submucosa tissue (SIS), or TFC absorbed to SIS. Blood flow in both limbs was assessed with laser Doppler perfusion imaging. Tissues harvested at Day 48 were assessed immunohistochemically for vessel density; in situ hybridization and quantitative real-time PCR were employed to determine miR-126 expression. RESULTS LDP ratios were significantly elevated, compared to placebo control, on day 28 in all treatment groups (p=0.0816, p=0.0543, p=0.0639, for groups 2-4, respectively) and on day 36 in the TFC group (p=0.0866). This effect correlated with capillary density in the SIS and TFC+SIS groups (p=0.0093 and p=0.0054, respectively, compared to placebo). A correlation was observed between miR-126 levels and LDP levels at 48 days in SIS and TFC+SIS groups. CONCLUSIONS A single bolus administration of TFC and SIS had early, transient effects on reperfusion and promotion of ischemia repair. The effects were not additive. We also discovered that TFC modulated miR-126 levels that were expressed in cell types other than endothelial cells. These data suggested that TFC, alone or in combination with SIS, may be a potent therapy for patients with CLI that are at risk of amputation.

Preclinical in Vitro and in Vivo Assessment of Linear and Branched l-Valine-Based Poly(ester urea)s for Soft Tissue Applications.

New polymers are needed to address the shortcomings of commercially available materials for soft tissue repair. Herein, we investigated a series of l-valine-based poly(ester urea)s (PEUs) that vary in monomer composition and the extent of branching as candidate materials for soft tissue repair. The preimplantation Young's moduli (105 ± 30 to 269 ± 12 MPa) for all the PEUs are comparable to those of polypropylene (165 ± 5 MPa) materials currently employed in hernia-mesh repair. The 2% branched poly(1-VAL-8) maintained the highest Young's modulus following 3 months of in vivo implantation (78 ± 34 MPa) when compared to other PEU analogues (20 ± 6-45 ± 5 MPa). Neither the linear or branched PEUs elicited a significant inflammatory response in vivo as noted by less fibrous capsule formation after 3 months of implantation (80 ± 38 to 103 ± 33 µm) relative to polypropylene controls (126 ± 34 µm). Mechanical degradation in vivo over three months, coupled with limited inflammatory response, suggests that l-valine-based PEUs are translationally relevant materials for soft tissue applications.

Exertional heat illness and acute injury related to ambient wet bulb globe temperature.

BACKGROUND: The Deepwater Horizon disaster cleanup effort provided an opportunity to examine the effects of ambient thermal conditions on exertional heat illness (EHI) and acute injury (AI). METHODS: The outcomes were daily person-based frequencies of EHI and AI. Exposures were maximum estimated WBGT (WBGTmax) and severity. Previous day's cumulative effect was assessed by introducing previous day's WBGTmax into the model. RESULTS: EHI and AI were higher in workers exposed above a WBGTmax of 20°C (RR 1.40 and RR 1.06/°C, respectively). Exposures above 28°C-WBGTmax on the day of the EHI and/or the day before were associated with higher risk of EHI due to an interaction between previous day's environmental conditions and the current day (RRs from 1.0-10.4). CONCLUSIONS: The risk for EHI and AI were higher with increasing WBGTmax. There was evidence of a cumulative effect from the prior day's WBGTmax for EHI. Am. J. Ind. Med. 59:1169-1176, 2016. © 2016 Wiley Periodicals, Inc.

Transforming surgery through biomaterial template technology.

Templates inserted into surgical wounds strongly influence the healing responses in humans. The science of these templates, in the form of extracellular matrix biomaterials, is rapidly evolving and improving as the natural interactions with the body become better understood.

Suppression and activation of the malignant phenotype by extracellular matrix in xenograft models of bladder cancer: a model for tumor cell "dormancy".

A major problem in cancer research is the lack of a tractable model for delayed metastasis. Herein we show that cancer cells suppressed by SISgel, a gel-forming normal ECM material derived from Small Intestine Submucosa (SIS), in flank xenografts show properties of suppression and re-activation that are very similar to normal delayed metastasis and suggest these suppressed cells can serve as a novel model for developing therapeutics to target micrometastases or suppressed cancer cells. Co-injection with SISgel suppressed the malignant phenotype of highly invasive J82 bladder cancer cells and highly metastatic JB-V bladder cancer cells in nude mouse flank xenografts. Cells could remain viable up to 120 days without forming tumors and appeared much more highly differentiated and less atypical than tumors from cells co-injected with Matrigel. In 40% of SISgel xenografts, growth resumed in the malignant phenotype after a period of suppression or dormancy for at least 30 days and was more likely with implantation of 3 million or more cells. Ordinary Type I collagen did not suppress malignant growth, and tumors developed about as well with collagen as with Matrigel. A clear signal in gene expression over different cell lines was not seen by transcriptome microarray analysis, but in contrast, Reverse Phase Protein Analysis of 250 proteins across 4 cell lines identified Integrin Linked Kinase (ILK) signaling that was functionally confirmed by an ILK inhibitor. We suggest that cancer cells suppressed on SISgel could serve as a model for dormancy and re-awakening to allow for the identification of therapeutic targets for treating micrometastases.

Augmenting myometrial healing after cesarean delivery: use of an adjuvant biologic graft placement in an ovine model.

We sought to reduce long-term complications after cesarean delivery by improving myometrial healing. Eight sheep (three with twins) underwent cesarean delivery. Hysterotomy sites were repaired in equal parts by suture alone or suture with a juxtaposed graft (Cook Medical, Bloomington, IN). At 90 days postsurgery, scar characteristics and tensile strength testing were assessed. The mean hysterotomy closure time was on average 1 minute, 14 seconds longer for those undergoing graft placement ( P=0.36). The mean scar thickness was 3.0 ± 0.4 mm for controls versus 3.8 ± 1.2 mm for the intervention group ( P=0.047). Tensile strength testing did not demonstrate a significant difference between groups. Histological examination of the myometrial scar showed no significant differences in inflammatory reaction or endometrial inclusions; however, neoangiogenesis was significantly enhanced. Myometrial repair incorporating a graft increased scar thickness and neoangiogenesis. This methodology did not incite adenomyosis or enhance inflammation within the scar.

Addition of nimesulide to small intestinal submucosa biomaterial inhibits postsurgical adhesiogenesis in rats.

Adhesion formation is a common complication in abdominal surgery with incidence as high as 93% and small bowel obstruction a common complication. Because the extracellular matrix material, small intestinal submucosa (SIS), is commonly used in various surgical procedures, methods to inhibit adhesiogenesis are of great interest. This study was undertaken to determine if incorporation of nimesulide (NM), a selective cyclooxygenase (COX)-2 inhibitor, could reduce the extent and tenacity of intraabdominal adhesion formation associated with SIS implantation. Female Sprague-Dawley rats underwent a cecal abrasion surgical procedure to induce adhesiogenesis. Rats were either left untreated or treated by direct application over the injured cecum with polypropylene mesh (PPM); SIS; SIS containing a low dose of NM; or SIS containing a high dose of NM. Rats were euthanized 21 days later, and adhesion extent and tenacity were evaluated using standard scales (0 = minimal adhesiogenesis; 4 = severe adhesiogenesis). Addition of NM to SIS resulted in a significant (p < 0.05) reduction in adhesion extent and in a similar reduction in adhesion tenacity for SIS containing a low dose of NM. Adhesions typically extended from the abraded cecal surface to the body wall and were characterized histologically by fibrous tissue adherent to the cecal wall. In conclusion, addition of the nonsteroidal anti-inflammatory, COX-2 selective drug, NM, to SIS attenuates adhesion extent and tenacity when compared with surgical placement of SIS or PPM alone.

Are biologic grafts effective for hernia repair?: a systematic review of the literature.

Biologic grafts for hernia repair are a relatively new development in the world of surgery. A thorough search of the Medline database for uses of various biologic grafts in hernia shows that the evidence behind their application is plentiful in some areas (ventral, inguinal) and nearly absent in others (parastomal). The assumption that these materials are only suited for contaminated or potentially contaminated surgical fields is not borne out in the literature, with more than 4 times the experience being reported in clean fields and the average success rates being higher (93% vs 87%). Outcomes prove to be highly dependent on material source, processing methods and implant scenarios with failure rates ranging from zero to more than 30%. Small intestinal submucosa (SIS) grafts have an aggregate failure rate of 6.7% at 19 months whereas acellular human dermis (AHD) grafts have a failure rate of 13.6% at 12 months. Chemically cross-linked grafts have much less published data than the non-cross-linked materials. In particular, the search found 33 articles for SIS, 32 for AHD, and 13 for cross-linked porcine dermis. Furthermore, the cumulative level of evidence for each graft material was fairly low (2.6 to 2.9), and only 1 material (SIS) had level 1 evidence reported in any hernia type (inguinal and hiatal). Together, biologic grafts have published evidence showing success rates better than 90% overall and more than 2000 years of cumulative implant time. Improvements in materials, techniques, and patient selection are likely to improve these numbers as this field of surgery matures.

Rapid biofabrication of tubular tissue constructs by centrifugal casting in a decellularized natural scaffold with laser-machined micropores.

Centrifugal casting allows rapid biofabrication of tubular tissue constructs by suspending living cells in an in situ cross-linkable hydrogel. We hypothesize that introduction of laser-machined micropores into a decellularized natural scaffold will facilitate cell seeding by centrifugal casting and increase hydrogel retention, without compromising the biomechanical properties of the scaffold. Micropores with diameters of 50, 100, and 200 mum were machined at different linear densities in decellularized small intestine submucosa (SIS) planar sheets and tubular SIS scaffolds using an argon laser. The ultimate stress and ultimate strain values for SIS sheets with laser-machined micropores with diameter 50 mum and distance between holes as low as 714 mum were not significantly different from unmachined control SIS specimens. Centrifugal casting of GFP-labeled cells suspended in an in situ cross-linkable hyaluronan-based hydrogel resulted in scaffold recellularization with a high density of viable cells inside the laser-machined micropores. Perfusion tests demonstrated the retention of the cells encapsulated within the HA hydrogel in the microholes. Thus, an SIS scaffold with appropriately sized microholes can be loaded with hydrogel encapsulated cells by centrifugal casting to give a mechanically robust construct that retains the cell-seeded hydrogel, permitting rapid biofabrication of tubular tissue construct in a "bioreactor-free" fashion.

Use of an extracellular matrix material as a vaccine carrier and adjuvant.

BACKGROUND: The addition of adjuvants frequently enhances the efficacy of vaccine preparations. Interest in the use of vaccines as a means to treat cancer has led to the search for improved adjuvants. Because cancer vaccines based on whole cell preparations might benefit from an adjuvant which enhances expression of antigens expressed during tumor cell growth, we evaluated the utility of an extracellular matrix material, porcine small intestinal submucosa (SIS), as a cancer vaccine adjuvant. MATERIALS AND METHODS: After tumors were produced in Lobund-Wistar (LW) rats by subcutaneous administration of PAIII prostate adenocarcinoma cells, rats underwent surgical debulking of the tumor mass. Groups of ten rats were then vaccinated directly on the tumor bed with glutaraldehyde-treated tumor (GFT) cells harvested from a PAIII tumor; a 2 x 2 cm section of glutaraldehyde-treated SIS; or a 2 x 2 cm section of SIS on which harvested tumor cells were grown for either 3 days (GFT-S3) or 28 days (GFT-S28) and then treated with glutaraldehyde. In addition, a group was left untreated after debulking. RESULTS: When tumors and lungs were harvested 21 days later, there were no significant differences between mean tumor weights of rats vaccinated with GFT cells or SIS and those which were left untreated. In contrast, rats vaccinated with GFT-S3 had a significant (p<0.01) reduction of greater than 65% and 58% in mean tumor weight compared to untreated rats and GFT cell-vaccinated rats, respectively. GFT-S28 rats had a significant (p<0.05) reduction of 59% and 49% compared to untreated rats and GFT cell-vaccinated rats, respectively. There was no significant difference in mean tumor weight between GFT-S3 and GFT-S28 rats. Furthermore, while most untreated rats had at least one metastatic focus in the lungs, a reduction was seen in rats vaccinated with GFT (7/10 positive), GFT-S3 (2/5 positive) and GFT-S28 (2/5 positive) cells. CONCLUSION: SIS enhanced the efficacy of a tissue vaccine for prostate cancer, demonstrating the potential utility of extracellular matrices as novel vaccine adjuvants.

Bioactivity of small intestinal submucosa and oxidized regenerated cellulose/collagen.

OBJECTIVE: This study examined the bioactivity of porcine small intestinal submucosa (SIS Wound Matrix [SISWM], USP) and oxidized regenerated cellulose/collagen (ORC). DESIGN: Bioactivity was assessed in vitro as the ability to stimulate neurite outgrowth in rat pheochromocytoma (PC12) cells, proliferation of human fibroblasts, secretion of vascular endothelial growth factor (VEGF) from human fibroblasts, and in an in vivo angiogenesis model. In the angiogenesis model, SISWM and ORC were implanted subcutaneously into the mice, and vessel ingrowth was assessed at day 21 after implantation using fluorescence microangiography and histology. MAIN OUTCOME MEASURES: The change in cellular differentiation, proliferation, growth factor secretion, and angiogenesis over the negative control was measured after exposure to SISWM or ORC. MAIN RESULTS: SISWM increased neurite outgrowth in PC12 cells by approximately 22% over negative controls and induced proliferation in 50.8% of human fibroblasts. These increases were comparable to positive controls. ORC was not active in either of these assays. SISWM also stimulated fibroblast VEGF secretion to a greater extent (422.4 pg/mL) than ORC (4.2 pg/mL) (P < .001). At 21 days, fluorescence microangiography showed dense infiltration of blood vessels in the SISWM that extended approximately 3 mm from the edge of the disc. In contrast, the ORC implant showed blood vessel incursion less than 1 mm from the edge of the disc, and it dissolved in the site. CONCLUSIONS: SISWM shows much greater bioactivity than ORC. This is likely related to its close structural and biochemical approximation to natural dermal extracellular matrix and may help explain the strong clinical successes of SISWM.

Absorption of bioactive molecules into OASIS wound matrix.

OBJECTIVE: To examine the ability of OASIS Wound Matrix to absorb, retain, and protect bioactive molecules from solution. DESIGN: Samples of OASIS Wound Matrix were incubated in solutions of bioactive molecules, specifically heparin, albumin, fibronectin, basic fibroblast growth factor 2, and platelet-derived growth factor (PDGF). Half of the samples were then rinsed, and all of the samples were evaluated using enzyme-linked immunosorbent assays (ELISAs) and dye-mediated spectrophotometric methods for absorption and retention of the bioactive molecules. Protection of PDGF was measured by placing PDGF-incubated and control samples into a degradation solution containing plasmin. Intact PDGF levels were then evaluated using a PDGF-specific ELISA. MAIN OUTCOME MEASURES: The main outcome measures were the amount of each bioactive molecule that was absorbed after incubation in solutions and retained after rinses as well as the amount of PDGF remaining after plasmin degradation. MAIN RESULTS: OASIS Wound Matrix absorbed bioactive molecules from solution, selectively absorbed PDGF from serum, and protected PDGF from protease degradation. CONCLUSIONS: Although OASIS Wound Matrix potentially has multiple functions in wound healing, it likely promotes wound healing, in part, by absorbing, retaining, and protecting bioactive molecules from the wound environment.

Effects of sterilization on an extracellular matrix scaffold: part II. Bioactivity and matrix interaction.

Small intestinal submucosa (SIS) has been successfully used to treat a variety of damaged or diseased tissues in human patients. As a biologic scaffold, SIS stimulates repair of damaged or diseased tissues and organs with tissue that is similar in structure and function to the material it was meant to replace. To meet clinical safety requirements, biologic materials from animal tissues must undergo processing treatments to minimize host immune response and to eliminate the possibility of disease transmission. The effect of peracetic acid disinfection, lyophilization, and ethylene oxide sterilization on the in vitro bioactivity of the processed SIS was therefore examined in murine fibroblasts and pheochromocytoma (PC12) cells. Specifically, the ability of processed SIS to support fibroblast attachment, to stimulate PC12 cell differentiation, and to upregulate fibroblast VEGF secretion was examined. Fibroblasts attach to the sterilized SIS, remain viable, and more than double their secretion of VEGF as a result of interacting with the SIS matrix components. Additionally, PC12 cells exhibit increased neurite outgrowth following stimulation by SIS matrix proteins versus controls. We conclude that a biologic scaffold can be prepared for human use and still retain significant bioactivity.

Tissue engineering a clinically useful extracellular matrix biomaterial.

Implantable biomaterials are one of the most useful tools in the surgeon's armamentarium, yet there is much room for improvement. Chronic pain, tissue erosion, and late infections are just a few of the serious complications that can occur with conventional, inert materials. In contrast, tissue-inductive materials exist today. Combinations of biologically important molecules for directing cell growth and providing structural stability can be found in naturally occuring extracellular matrices. These "soft-tissue skeletons" of Mother Nature can be harvested, processed, and provided in a medically safe and biologically active form for repairing many different tissues in the human body. The future of surgical practice may well be determined by how well these new implant materials recreate the tissues they replace.

Interactive biomaterials: taking surgery to the next level.

Medicine has been advanced greatly by implantable biomaterials, but today's standard materials are not without problems. Infection, erosion, adhesions, persistent pain, and other complications suggest that something better is possible. Just as normal tissues self-renew, it is desirable to have an implant recapitulate original anatomy for both structure and function. Short of complete tissue regeneration, perhaps an implant material could transition from an inanimate bridge to a living tissue with strong similarity to the original host architecture-to optimize the biology and not simply the mechanics of tissue repair. Such remodelable or tissue-inductive materials exist today and are in use in a wide variety of surgical applications. Changing the idea that implants must be rigid, inert, and permanent to an understanding that implants can provide short-term mechanics and long-term repair by harnessing the host's healing abilities represents a paradigm shift that will ultimately benefit patients and the practice of surgery.