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Ann. N.Y. Acad. Sci. 961: 319–322 (2002). © 2002 New York Academy of Sciences.

In Vivo Remodeling

Breakout Session Summary

Moderators

STEPHEN F. BADYLAK, Purdue University

MARKUS GROMPE, Oregon Health and Science University

Panelists

ARNOLD I. CAPLAN, Case Western Reserve University

HOWARD P. GREISLER, Loyola University Medical Center

ROBERT E. GULDBERG, Georgia Institute of Technology

DORIS A. TAYLOR, Duke University Medical Center

Rapporteur

STEPHEN F. BADYLAK

BROAD STATEMENT

The implantation of tissue-engineered devices or cells into living hosts is accom-panied by unavoidable remodeling of both the implant and the host tissue. Tissue re-modeling is a dynamic process that is related to normal developmental biology andis present from the earliest moments of fetal development. In the adult, this processexists as part of the tissue repair response and can result in several possible outcomesincluding tissue regeneration, scar tissue formation, or complete tissue loss.

VISION

An in-depth understanding of the signals and mechanisms that control this pro-cess at the molecular level is necessary to maximize the constructive outcomes andtherapeutic applications that can potentially result from in vivo remodeling. The pat-terns of in vivo remodeling differ among species, within species, and even as a func-tion of age or body location within the same individual. The remodeling events arefundamentally protective responses against tissue injury or tissue exposure to harm-ful substances, and thus are attempts to assure survival of both the individual and thespecies. Efforts to understand the molecular signals that control the remodeling pro-cess will have multiple positive payoffs, including an improved understanding of de-velopmental biology, inflammation and immunity, scar tissue formation, tissue andorgan regeneration, and wound healing.

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OBJECTIVES

In vivo remodeling is the inevitable fate of all efforts at tissue engineering and re-parative medicine. Regardless of whether the therapeutic approach is gene- or cell-based, scaffold-based, or based upon the use of selected growth factors or a combi-nation approach, it will be subjected to the biologic variability that is part of in vivoremodeling. All events that precede the in vivo step, including the selection of spe-cific cell types, the in vitro cell or tissue bioreactor conditions, and the utilization ofdesired scaffold materials, can generally be tightly controlled. However, the in vivoremodeling that occurs after application to the mammalian system has much lesspredictable results based upon our current knowledge base and current methodolo-gies. Goals of research in this area should include:

(1) Characterization at the molecular level of the differences between woundhealing events that occur at different ages; especially the differences between fetalvs. adult wound healing. The rationale for this goal is that the genetic makeup of anindividual is constant throughout life, yet tissue response to injury can differ mark-edly between the fetus and the adult. Fetal wounds can heal with complete regener-ation of tissues and organs, whereas adults tend to heal by scar tissue formation or,in selected instances, wound healing can fail completely. What are the specific dif-ferences in this wound healing response? What molecular signals control these dif-ferences based upon age of the individual? Can these signals be modified bytherapeutic intervention? Without a thorough understanding of these issues, it islikely that only incremental advances will be made in this field.

(2) Understanding at the molecular level the differences between wound healingin normal and diseased individuals. The rationale for this goal is that reparative med-icine and tissue-engineering efforts are targeted at the repair and restoration of dam-aged or missing tissues and organs. By definition, therefore, these efforts will betargeted at otherwise healthy individuals with congenital deformities, healthy indi-viduals with traumatic injuries, and diseased individuals with degenerative, inflam-matory, or neoplastic conditions. It is important to understand the differences thatmay exist in the in vivo remodeling events for these different conditions. Even if thetherapeutic methods that are considered optimal are utilized for all of these differentstates, it is unlikely that the short- and long-term expectations for success will be thesame.

(3) An understanding at the molecular level of the events that control and regulatethe formation of scar tissue; especially in the nervous system. The rationale for thisgoal is that scar tissue formation is a common result of in vivo remodeling followingtissue injury in the adult. Scar tissue is the bane of surgeons and is associated withloss of tissue or organ function, undesirable adhesions, and less than optimal cosmet-ic results. Scar tissue is considered to be one of the major barriers to regeneration ofcentral and peripheral nerve tissue. The formation of scar tissue has significantlymore detrimental sequelae in the central nervous system than in other body systemssuch as the integumentary system or musculoskeletal system. An understanding ofthe controlling signals for scar tissue formation is essential before therapeutic meth-ods can be developed to minimize or eliminate it.

321IN VIVO REMODELING: BREAKOUT SESSION SUMMARY

OBSTACLES

Several significant obstacles exist to a more thorough understanding of the eventsthat regulate in vivo remodeling in mammalian systems. Identification and enumer-ation of these obstacles will permit the development of a rational approach to over-coming these limitations and provide for advancement in the field. These obstaclesprovide targets for future resource deployment. Although the following list is by nomeans comprehensive, it represents the panel’s collective opinion as to the mostdominant current rate-limiting issues:

(1) Methods to quantitatively and qualitatively study gene expression in hostand donor cells at the single-cell level are poorly developed. Until suchmethods can be developed, it will be very difficult to make significantprogress in our understanding of normal developmental biology events, themammalian response to tissue injury, transplanted cells, or foreign materi-als (e.g., scaffolds), or the regulators of cellular proliferation, hypertrophy,differentiation or spatial three-dimensional organization.

(2) Inter-individual biologic variability in higher mammals makes controlledstudy of the events that regulate in vivo remodeling very difficult.The rea-sons for the differences in in vivo remodeling events following the sametissue injury in separate individuals is very poorly understood. Are thesedifferences in the rate of remodeling or the extent of remodeling or theeffects of nutrition or age inevitable? Can these differences be controlled?The presence of this biologic variability makes controlled study design dif-ficult and expensive. This variability also raises significant questions withregard to choice of animal models for particular types of tissue injury.

(3) There is a paucity of methods for tracking the fate of implanted tissue engi-neered genes, cells, scaffolds and composite devices in real time. The abil-ity to monitor in real time the fate of cells or scaffolds, gene expressionpatterns, and the degradation of implanted tissue-engineered devices isessential to the iterative research process and thus, to progress in the field.

CHALLENGES

A concerted multidisciplinary effort to identify and understand the molecularevents that control wound healing, especially the differences in wound healing be-tween the fetus and the adult, is imperative. Such an effort will likely require thecombined and coordinated efforts of molecular biologists, developmental biologists,and tissue engineers. Such an effort should be inclusive of individuals not only withspecialized expertise in selected basic science fields, but also those individuals withknowledge of the translational efforts necessary to quickly mobilize this knowledgeto the tissue-engineering laboratory and the bedside. An understanding, at the mo-lecular level, of those controlling events that result in constructive remodeling of tis-sues vs. those that result in destructive remodeling or lack of remodeling isnecessary.

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It is likely that the traditional dividing lines that tend to exist between our under-standing of the processes of inflammation, immunity, scar tissue formation, devel-opmental biology, and wound healing will require rethinking and/or elimination. Invivo remodeling incorporates all of these events simultaneously. Understanding thesimilarities and differences in these events will allow the design of rational cell,gene, scaffold or combination approaches as therapeutic methods.

Development of improved methods to track the fate of implanted tissue-engi-neered devices is needed. These methods should include strategies for monitoringthe ultimate fate of implanted cells, degradation of implanted scaffolds, and quanti-tative expression of specific genes. It is likely that autologous, allogeneic, and xeno-geneic genetic material, cells, and scaffold materials will have potential benefit infuture strategies for reparative medicine. Furthermore, both synthetic and naturallyoccurring materials are likely to have roles in optimal therapeutic modalities. The bi-ologic fate of these products is of critical importance in the development of rationaltreatment methods. Without the tools to track the in vivo fate of these products andthe function of the target tissue or organ, progress will be severely limited.

And, finally, it is recommended that a registry of human patients that receivetissue-engineered products be developed. This database should include such infor-mation as gender, ethnic background, selected genotypic information, age, and stateof health/disease. This information can be used to later establish predictors of suc-cess and failure for tissue-engineered products.

ACKNOWLEDGMENTS

The in Vivo Remodeling Breakout Session was coordinated by Dr. Arlene Chiu(NINDS, NIH) and Dr. Nancy Freeman (NIDCD, NIH).