Complexity in biomaterials for tissue engineering

Complexity in biomaterials for tissue engineering

(Parte 1 de 6)

nature materials | VOL 8 | JUNE 2009 | 457 review article Published online: 21 may 2009 | doi: 10.1038/nmat2441

A human embryo in its first eight weeks of life undergoes an extraordinary transformation from a single cell to a 3-cmlong fetus with a beating heart, gut, nervous system, and limbs with fingers and toes. This progression involves massive growth, physical folds and twists, and myriad cellular and molecular events of breathtaking complexity; yet it is the ultimate goal of tissue engineering (TE) to recreate some of these processes in microcosm, to replace and regenerate lost tissue. At last the field has entered a period of fruition, and seems set to realize its potential to treat a multitude of debilitating and deadly conditions such as myocardial infarction, spinal injury, osteoarthritis, osteoporosis, diabetes, liver cirrhosis and retinopathy. The general strategy is usually to seed cells within a scaffold, a structural device that defines the geometry of the replacement tissue and provides environ mental cues that promote tissue regeneration. TE skin equivalents have been in clinical use since 1997 (ref. 1) and a fast-growing arsenal of replacement devices is in clinical trials or already approved as therapies for tissues including cartilage, bone, blood vessel and pancreas (Table 1). In two recent high-profile studies, seven patients benefited from TE bladders2, and a 30-year-old woman became the first person to receive a TE tracheal segment, a procedure that saved her left lung3.

Aside from the obvious human benefits, tissue engineering could bring substantial financial rewards to those who succeed in translating this new technology to the clinic. Sales of regenerative biomaterials already exceed US$240 million per annum4 and the wider markets that tissue engineering taps into are colossal: costs related to organ replacement account for 8% of global healthcare spending, and by 2040 as much as 25% of the US GDP is expected to be related to healthcare5. Nevertheless, if the short history of industrial tissue engineering has taught us anything, it is that the provision of effective products is not in itself sufficient to ensure commercial success (Fig. 1). Early TE efforts were plagued by product issues related to scale-up, shelf-life, quality control and distribution, and suffered from inappropriate business models and withdrawal of private finance in the early 2000s1,6. Since then the field has matured, evidenced by the return of large-scale investment and the first regenerative medicine companies becoming profitable4.

Alongside these positive developments, progress in biomaterials design and engineering are converging to enable a new generation of instructive materials to emerge as candidates for regenerative medicine. Which of these materials compete successfully in the market will depend on a combination of clinical performance, marketing and cost-effectiveness. A central dilemma is that to influence cell behaviour, scaffolding materials must bear complex information,

Complexity in biomaterials for tissue engineering elsie s. Place1,2, nicholas d. evans1,2 and molly m. stevens1,2

The molecular and physical information coded within the extracellular milieu is informing the development of a new generation of biomaterials for tissue engineering. Several powerful extracellular influences have already found their way into cellinstructive scaffolds, while others remain largely unexplored. Yet for commercial success tissue engineering products must be not only efficacious but also cost-effective, introducing a potential dichotomy between the need for sophistication and ease of production. This is spurring interest in recreating extracellular influences in simplified forms, from the reduction of biopolymers into short functional domains, to the use of basic chemistries to manipulate cell fate. In the future these exciting developments are likely to help reconcile the clinical and commercial pressures on tissue engineering.

coded in their physical and chemical structures. On the other hand, financial considerations dictate that complexity must be kept to a minimum. Clearly there is a danger, by over-engineering devices, of making their translation to clinical use unlikely. The solutions to this challenge lie at every phase of product development, beginning with identifying the simplest functional performance required to resolve a defined clinical problem. The ambitious early aims of reconstructing entire organs have largely given way to smaller, more attainable goals: for example, rather than trying to replace an entire heart, clinical advances in cardiac repair focus on TE coronary arteries, valves and myocardium. Organogenesis Inc. and Advanced Tissue Sciences Inc. suffered heavily as a result of their overestimating the number of chronic wounds cases that were best solved by high-tech, TE skin substitutes (respectively, Apligraf and Dermagraft; Dermagraft is now produced by Advanced Biohealing) as opposed to acellular products that aid ongoing repair6 (Table 1, Fig. 1). Similarly, an emerging philosophy in tissue engineering is that rather than attempting to recreate the complexity of living tissues ex vivo, we should aim to develop synthetic materials that establish key interactions with cells in ways that unlock the body’s innate powers of organization and self-repair. In this review we will consider how this can be achieved, emphasizing how even relatively simple engineering solutions can deliver considerable functional benefits. Along the way we will explore how some of these principles have been applied to specific scientific and commercial tissueengineering challenges.

regenerative potential of tissues Even without any therapeutic intervention, living tissues can have a staggering capacity for regeneration. For example, the human liver will regrow to its original size even when more than 50% of its mass is excised7. This has been taken to the extreme in rats, where one group has reported that a single rat’s liver was able to regenerate fully following each of 12 sequential hepatectomies, a finding that can be explained by the high replicative potential of the cell types that make up the liver. Several other tissues — bone and skin, for example — also have an innate capacity to regenerate to fill injuries below a critical size, helped by local or recruited stem cells. The clinical potential of stem cells has long been recognized by haemato logists, who in the 1960s showed that transplanted haemato poietic (literally ‘blood-making’) stem cells from the bone marrow of a healthy mouse could replace the destroyed immune system of another mouse, paving the way for a cure for leukaemia8,9. The discovery of other types of cell with multilineage Department of Materials; Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, UK. e‑mail:

458 nature materials | VOL 8 | JUNE 2009 | review articleNaTure maTerIalS doi: 10.1038/nmat2441 potential has since followed, including neural stem cells from the brain, and mesenchymal stem cells, which can differentiate into bone, fat, cartilage and muscle cells10,1. Indeed, more recent evidence suggests that stem cells or progenitor cells can be isolated from almost every tissue of the body12,13. Under the correct conditions, these cells can be stimulated to form new tissue, as we recently demonstrated using a simple biomaterials-based approach. Here, either calcium-crosslinked alginate gels or modified hyaluronic acid gels were injected into an artificial space between the tibia and the periosteum, the fibrous outer lining of bone. This stimulated bone and cartilage formation from resident progenitor cells in the inner layer of the periosteum14, illustrating that complex tissues can be generated from relatively simple materials by using the body as a ‘bioreactor’.

Table 1 | Commercial tissue engineering products and biomaterials at various stages of development.

tissue Product regulatory status description material Cells use Form

S ynthetic r esorbable a nimal deriv ed

Plant or bacteria deriv ed

Human deriv ed o wth f act a llog enic a ut olog ous

SkinTransCyte, Advanced Biohealing 1997Nylon mesh coated with porcine collagen, containing non‑viable human fibroblasts, with upper layer of silicon

Apligraf, Organogenesis1998Lower layer of human fibroblasts and bovine collagen, upper layer of keratinocytes

Dermagraft, Advanced BioHealing 2001Cryopreserved human fibroblasts on a polyglactin 910 (2‑hydroxy‑propanoic acid polymer with polymerized hydroxyacetic acid) mesh

✓✓✓Diabetic foot ulcers Sheet

ICX‑SKN, IntercytexPhase IIAllogenic fibroblasts and human collagen with additional layer of keratinocytes

✓✓✓Burns and acute wounds Sheet

Integra Dermal Regeneration Template, Integra Lifesciences

1996Porous bovine collagen crosslinked with chondroitin‑6‑sulphate with upper layer of silicon

Integra Flowable Wound Matrix, Integra Lifesciences 2007Granulated bovine collagen crosslinked with chondroitin‑6‑sulphate

✓ ✓ Ulcers Gel

Oasis Wound Matrix, Healthpoint 2006Decellularized porcine small intestinal submucosa

✓✓Burns, ulcers, other wounds Sheet

PriMatrix, TEI Biosciences2008Decellularized fetal bovine skin✓✓WoundsSheet

Xelma, Molnlycke2005 EUECM protein (amelogenins) in propylene glycol alginate carrier ✓✓✓Leg ulcersGel

BoneINFUSE Bone Graft,

Medtronic 2002Bovine type I collagen sponges soaked in rhBMP‑2 in LT‑CAGE Lumbar Tapered Fusion Device

OP‑1, Stryker2001Bovine type I collagen with rhBMP‑7✓✓✓Bone injuryPaste

PuraMatrix, 3DMPreclinicSynthetic 16‑amino‑acid peptide, forming nanofibres

✓✓Dental bone defects Gel

Vitoss Scaffold FOAM, Orthovita 2004Porous foam comprising β‑TCP and bovine type I collagen ✓✓✓Bone injuryFoam

Bioset IC, Pioneer surgical2008Human demineralized bone matrix with bovine bone chips in type I collagen carrier

FortrOss, Pioneer Surgical2008Nanocrystalline hydroxyapatite and E‑matrix (porcine collagen co‑polymerized with dextran)

✓✓✓✓Bone injuryPaste

Regenafil, Regeneration Technologies/Exatech 2005Human mineralized bone matrix in porcine gelatin carrier ✓✓✓Bone injuryPaste

GEM 21S, BioMimetic Therapeutics 2005β‑TCP particles and recombinant human platelet‑derived growth factor‑B (PDGF‑B)

✓✓✓Dental bone/ gum defects Paste

BCT001, Bioceramic Therapeutics

PreclinicStrontium releasing bioactive glasses✓✓Bone defectsGranules, paste nature materials | VOL 8 | JUNE 2009 | 459 review articleNaTure maTerIalS doi: 10.1038/nmat2441

Such simple strategies unfortunately do not offer a universal regenerative solution. Healing may be restricted by an age-related decline in progenitor populations, by the intrinsically low regenerative potential of certain tissues, or by scarring or inflammation, such as follows myocardial infarction in the heart or stroke in the brain. In these cases, or where the original tissue has been completely destroyed, biomaterials interventions that include an external source of cells may be required. Over 700 adult stem-cell therapies are

Table 1 (continued) | Commercial tissue engineering products and biomaterials at various stages of development.

tissue Product regulatory status description material Cells use Form

S ynthetic r esorbable a nimal deriv ed

Plant or bacteria deriv ed

Human deriv ed o wth f act a llog enic a ut olog ous

CartilageSynvisc, Genzyme1997Hyaluronic acid (Hylan GF‑20 and

Hylan B) from chicken combs

✓✓Synovial fluid replacement Gel

(Parte 1 de 6)